Publications by authors named "Matteo Pellegrini"

311 Publications

Development of allogeneic HSC-engineered iNKT cells for off-the-shelf cancer immunotherapy.

Cell Rep Med 2021 Nov 16;2(11):100449. Epub 2021 Nov 16.

Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Cell-based immunotherapy has become the new-generation cancer medicine, and "off-the-shelf" cell products that can be manufactured at large scale and distributed readily to treat patients are necessary. Invariant natural killer T (iNKT) cells are ideal cell carriers for developing allogeneic cell therapy because they are powerful immune cells targeting cancers without graft-versus-host disease (GvHD) risk. However, healthy donor blood contains extremely low numbers of endogenous iNKT cells. Here, by combining hematopoietic stem cell (HSC) gene engineering and differentiation, we generate human allogeneic HSC-engineered iNKT (HSC-iNKT) cells at high yield and purity; these cells closely resemble endogenous iNKT cells, effectively target tumor cells using multiple mechanisms, and exhibit high safety and low immunogenicity. These cells can be further engineered with chimeric antigen receptor (CAR) to enhance tumor targeting or/and gene edited to ablate surface human leukocyte antigen (HLA) molecules and further reduce immunogenicity. Collectively, these preclinical studies demonstrate the feasibility and cancer therapy potential of HSC-iNKT cell products and lay a foundation for their translational and clinical development.
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http://dx.doi.org/10.1016/j.xcrm.2021.100449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8607011PMC
November 2021

Hematopoiesis under telomere attrition at the single-cell resolution.

Nat Commun 2021 Nov 25;12(1):6850. Epub 2021 Nov 25.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. In light of recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells under telomere attrition, as induced by pathogenic germline variants in telomerase complex genes. Here, we show that telomere attrition maintains hematopoietic stem cells under persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of the innate immune signaling response, which directly compromises hematopoietic stem cells' self-renewal capabilities and eventually leads to their exhaustion. Mechanistically, we demonstrate that targeting members of the Ifi20x/IFI16 family of cytosolic DNA sensors using the oligodeoxynucleotide A151, which comprises four repeats of the TTAGGG motif of the telomeric DNA, overcomes interferon signaling activation in telomere-dysfunctional hematopoietic stem cells and these cells' skewed differentiation towards the megakaryocytic lineage. This study challenges the historical hypothesis that telomere attrition limits the proliferative potential of hematopoietic stem cells by inducing apoptosis, autophagy, or senescence, and suggests that targeting IFI16 signaling axis might prevent hematopoietic stem cell functional decline in conditions affecting telomere maintenance.
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http://dx.doi.org/10.1038/s41467-021-27206-7DOI Listing
November 2021

The cardiomyocyte disrupts pyrimidine biosynthesis in non-myocytes to regulate heart repair.

J Clin Invest 2021 Nov 23. Epub 2021 Nov 23.

Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, United States of America.

Various population of cells are recruited to the heart after cardiac injury but little is known about whether the cardiomyocyte directly regulates heart repair. In a murine model of ischemic cardiac injury, we demonstrate that the cardiomyocyte plays a pivotal role in heart repair by regulating nucleotide metabolism and fates of non-myocytes. Cardiac injury induced the expression of the ectonucleotidase ENPP1 that hydrolyzes extracellular ATP to form AMP. In response to AMP, the cardiomyocyte released adenine and specific ribonucleosides that disrupted pyrimidine biosynthesis at OMP synthesis step, induced genotoxic stress and a p53 mediated cell death of cycling non-myocytes. As non-myocytes are critical for heart repair, we showed that rescue of pyrimidine biosynthesis by administration of uridine or by genetic targeting of ENPP1/AMP pathway enhanced repair after cardiac injury. We identified ENPP1 inhibitors on small molecule screening and showed that systemic administration of an ENPP1 inhibitor after heart injury rescued pyrimidine biosynthesis in non-myocyte cells, augmented cardiac repair and post infarct heart function. These observations demonstrate that the cardiac muscle cell by releasing adenine and specific nucleosides after heart injury regulates pyrimidine metabolism in non-muscle cells and provide insight into how inter-cellular regulation of pyrimidine biosynthesis can be targeted and monitored for augmenting tissue repair.
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http://dx.doi.org/10.1172/JCI149711DOI Listing
November 2021

The IntAct database: efficient access to fine-grained molecular interaction data.

Nucleic Acids Res 2021 Nov 11. Epub 2021 Nov 11.

European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, Cambridgeshire CB10 1SD, UK.

The IntAct molecular interaction database (https://www.ebi.ac.uk/intact) is a curated resource of molecular interactions, derived from the scientific literature and from direct data depositions. As of August 2021, IntAct provides more than one million binary interactions, curated by twelve global partners of the International Molecular Exchange consortium, for which the IntAct database provides a shared curation and dissemination platform. The IMEx curation policy has always emphasised a fine-grained data and curation model, aiming to capture the relevant experimental detail essential for the interpretation of the provided molecular interaction data. Here, we present recent curation focus and progress, as well as a completely redeveloped website which presents IntAct data in a much more user-friendly and detailed way.
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http://dx.doi.org/10.1093/nar/gkab1006DOI Listing
November 2021

Synergistic Effects of Genetic Variants of Glucose Homeostasis and Lifelong Exposures to Cigarette Smoking, Female Hormones, and Dietary Fat Intake on Primary Colorectal Cancer Development in African and Hispanic/Latino American Women.

Front Oncol 2021 7;11:760243. Epub 2021 Oct 7.

Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.

Background: Disparities in cancer genomic science exist among racial/ethnic minorities. Particularly, African American (AA) and Hispanic/Latino American (HA) women, the 2 largest minorities, are underrepresented in genetic/genome-wide studies for cancers and their risk factors. We conducted on AA and HA postmenopausal women a genomic study for insulin resistance (IR), the main biologic mechanism underlying colorectal cancer (CRC) carcinogenesis owing to obesity.

Methods: With 780 genome-wide IR-specific single-nucleotide polymorphisms (SNPs) among 4,692 AA and 1,986 HA women, we constructed a CRC-risk prediction model. Along with these SNPs, we incorporated CRC-associated lifestyles in the model of each group and detected the topmost influential genetic and lifestyle factors. Further, we estimated the attributable risk of the topmost risk factors shared by the groups to explore potential factors that differentiate CRC risk between these groups.

Results: In both groups, we detected IR-SNPs in (in AA) and , , and (in HA) and risk lifestyles, including long lifetime exposures to cigarette smoking and endogenous female hormones and daily intake of polyunsaturated fatty acids (PFA), as the topmost predictive variables for CRC risk. Combinations of those top genetic- and lifestyle-markers synergistically increased CRC risk. Of those risk factors, dietary PFA intake and long lifetime exposure to female hormones may play a key role in mediating racial disparity of CRC incidence between AA and HA women.

Conclusions: Our results may improve CRC risk prediction performance in those medically/scientifically underrepresented groups and lead to the development of genetically informed interventions for cancer prevention and therapeutic effort, thus contributing to reduced cancer disparities in those minority subpopulations.
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http://dx.doi.org/10.3389/fonc.2021.760243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8529283PMC
October 2021

Fasting-mimicking diet prevents high-fat diet effect on cardiometabolic risk and lifespan.

Nat Metab 2021 10 14;3(10):1342-1356. Epub 2021 Oct 14.

Longevity Institute and Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.

Diet-induced obesity is a major risk factor for metabolic syndrome, diabetes and cardiovascular disease. Here, we show that a 5-d fasting-mimicking diet (FMD), administered every 4 weeks for a period of 2 years, ameliorates the detrimental changes caused by consumption of a high-fat, high-calorie diet (HFCD) in female mice. We demonstrate that monthly FMD cycles inhibit HFCD-mediated obesity by reducing the accumulation of visceral and subcutaneous fat without causing loss of lean body mass. FMD cycles increase cardiac vascularity and function and resistance to cardiotoxins, prevent HFCD-dependent hyperglycaemia, hypercholesterolaemia and hyperleptinaemia and ameliorate impaired glucose and insulin tolerance. The effect of monthly FMD cycles on gene expression associated with mitochondrial metabolism and biogenesis in adipocytes and the sustained ketogenesis in HFCD-fed mice indicate a role for fat cell reprogramming in obesity prevention. These effects of an FMD on adiposity and cardiac ageing could explain the protection from HFCD-dependent early mortality.
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http://dx.doi.org/10.1038/s42255-021-00469-6DOI Listing
October 2021

Molecular Biology Networks and Key Gene Regulators for Inflammatory Biomarkers Shared by Breast Cancer Development: Multi-Omics Systems Analysis.

Biomolecules 2021 09 18;11(9). Epub 2021 Sep 18.

Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.

As key inflammatory biomarkers C-reactive protein (CRP) and interleukin-6 (IL6) play an important role in the pathogenesis of non-inflammatory diseases, including specific cancers, such as breast cancer (BC). Previous genome-wide association studies (GWASs) have neither explained the large proportion of genetic heritability nor provided comprehensive understanding of the underlying regulatory mechanisms. We adopted an integrative genomic network approach by incorporating our previous GWAS data for CRP and IL6 with multi-omics datasets, such as whole-blood expression quantitative loci, molecular biologic pathways, and gene regulatory networks to capture the full range of genetic functionalities associated with CRP/IL6 and tissue-specific key drivers (KDs) in gene subnetworks. We applied another systematic genomics approach for BC development to detect shared gene sets in enriched subnetworks across BC and CRP/IL6. We detected the topmost significant common pathways across CRP/IL6 (e.g., immune regulatory; chemokines and their receptors; interferon γ, JAK-STAT, and ERBB4 signaling), several of which overlapped with BC pathways. Further, in gene-gene interaction networks enriched by those topmost pathways, we identified KDs-both well-established (e.g., JAK1/2/3, STAT3) and novel (e.g., CXCR3, CD3D, CD3G, STAT6)-in a tissue-specific manner, for mechanisms shared in regulating CRP/IL6 and BC risk. Our study may provide robust, comprehensive insights into the mechanisms of CRP/IL6 regulation and highlight potential novel genetic targets as preventive and therapeutic strategies for associated disorders, such as BC.
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http://dx.doi.org/10.3390/biom11091379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469138PMC
September 2021

Identification of Genes Encoding Antimicrobial Proteins in Langerhans Cells.

Front Immunol 2021 26;12:695373. Epub 2021 Aug 26.

Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.

Langerhans cells (LCs) reside in the epidermis where they are poised to mount an antimicrobial response against microbial pathogens invading from the outside environment. To elucidate potential pathways by which LCs contribute to host defense, we mined published LC transcriptomes deposited in GEO and the scientific literature for genes that participate in antimicrobial responses. Overall, we identified 31 genes in LCs that encode proteins that contribute to antimicrobial activity, ten of which were cross-validated in at least two separate experiments. Seven of these ten antimicrobial genes encode chemokines, and , which mediate both antimicrobial and inflammatory responses. Of these, was detected in seven of nine transcriptomes and by PCR in cultured LCs. Overall, the antimicrobial genes identified in LCs encode proteins with broad antibacterial activity, including against , which is the leading cause of skin infections. Thus, this study illustrates that LCs, consistent with their anatomical location, are programmed to mount an antimicrobial response against invading pathogens in skin.
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http://dx.doi.org/10.3389/fimmu.2021.695373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426439PMC
August 2021

The induction of preterm labor in rhesus macaques is determined by the  strength of immune response to intrauterine infection.

PLoS Biol 2021 09 8;19(9):e3001385. Epub 2021 Sep 8.

Divisions of Neonatology and Developmental Biology, UCLA Mattel Children's Hospital, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.

Intrauterine infection/inflammation (IUI) is a major contributor to preterm labor (PTL). However, IUI does not invariably cause PTL. We hypothesized that quantitative and qualitative differences in immune response exist in subjects with or without PTL. To define the triggers for PTL, we developed rhesus macaque models of IUI driven by lipopolysaccharide (LPS) or live Escherichia coli. PTL did not occur in LPS challenged rhesus macaques, while E. coli-infected animals frequently delivered preterm. Although LPS and live E. coli both caused immune cell infiltration, E. coli-infected animals showed higher levels of inflammatory mediators, particularly interleukin 6 (IL-6) and prostaglandins, in the chorioamnion-decidua and amniotic fluid (AF). Neutrophil infiltration in the chorio-decidua was a common feature to both LPS and E. coli. However, neutrophilic infiltration and IL6 and PTGS2 expression in the amnion was specifically induced by live E. coli. RNA sequencing (RNA-seq) analysis of fetal membranes revealed that specific pathways involved in augmentation of inflammation including type I interferon (IFN) response, chemotaxis, sumoylation, and iron homeostasis were up-regulated in the E. coli group compared to the LPS group. Our data suggest that the intensity of the host immune response to IUI may determine susceptibility to PTL.
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http://dx.doi.org/10.1371/journal.pbio.3001385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452070PMC
September 2021

NOTUM promotes thermogenic capacity and protects against diet-induced obesity in male mice.

Sci Rep 2021 08 12;11(1):16409. Epub 2021 Aug 12.

Department of Microbiology, Immunology, and Molecular Genetics, Division of Cardiology, Department of Medicine, Department of Human Genetics, University of California, 10833 Le Conte Avenue, A2-237 CHS, Los Angeles, CA, 90095-1679, USA.

We recently showed that NOTUM, a liver-secreted Wnt inhibitor, can acutely promote browning of white adipose. We now report studies of chronic overexpression of NOTUM in liver indicating that it protects against diet-induced obesity and improves glucose homeostasis in mice. Adeno-associated virus (AAV) vectors were used to overexpress GFP or mouse Notum in the livers of male C57BL/6J mice and the mice were fed an obesifying diet. After 14 weeks of high fat, high sucrose diet feeding, the AAV-Notum mice exhibited decreased obesity and improved glucose tolerance compared to the AAV-GFP mice. Gene expression and immunoblotting analysis of the inguinal fat and brown fat revealed increased expression of beige/brown adipocyte markers in the AAV-Notum group, suggesting enhanced thermogenic capacity by NOTUM. A β3 adrenergic receptor agonist-stimulated lipolysis test suggested increased lipolysis capacity by NOTUM. The levels of collagen and C-C motif chemokine ligand 2 (CCL2) in the epididymal white adipose tissue of the AAV-Notum mice were significantly reduced, suggesting decreased fibrosis and inflammation, respectively. RNA sequencing analysis of inguinal white adipose of 4-week chow diet-fed mice revealed a highly significant enrichment of extracellular matrix (ECM) functional cluster among the down-regulated genes in the AAV-Notum group, suggesting a potential mechanism contributing to improved glucose homeostasis. Our in vitro studies demonstrated that recombinant human NOTUM protein blocked the inhibitory effects of WNT3A on brown adipocyte differentiation. Furthermore, NOTUM attenuated WNT3A's effects on upregulation of TGF-β signaling and its downstream targets. Overall, our data suggest that NOTUM modulates adipose tissue function by promoting thermogenic capacity and inhibiting fibrosis through inhibition of Wnt signaling.
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http://dx.doi.org/10.1038/s41598-021-95720-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361163PMC
August 2021

Systematic evaluation of transcriptomics-based deconvolution methods and references using thousands of clinical samples.

Brief Bioinform 2021 Nov;22(6)

Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, 1540 Alcazar Street, Los Angeles, CA 90033, USA.

Estimating cell type composition of blood and tissue samples is a biological challenge relevant in both laboratory studies and clinical care. In recent years, a number of computational tools have been developed to estimate cell type abundance using gene expression data. Although these tools use a variety of approaches, they all leverage expression profiles from purified cell types to evaluate the cell type composition within samples. In this study, we compare 12 cell type quantification tools and evaluate their performance while using each of 10 separate reference profiles. Specifically, we have run each tool on over 4000 samples with known cell type proportions, spanning both immune and stromal cell types. A total of 12 of these represent in vitro synthetic mixtures and 300 represent in silico synthetic mixtures prepared using single-cell data. A final 3728 clinical samples have been collected from the Framingham cohort, for which cell populations have been quantified using electrical impedance cell counting. When tools are applied to the Framingham dataset, the tool Estimating the Proportions of Immune and Cancer cells (EPIC) produces the highest correlation, whereas Gene Expression Deconvolution Interactive Tool (GEDIT) produces the lowest error. The best tool for other datasets is varied, but CIBERSORT and GEDIT most consistently produce accurate results. We find that optimal reference depends on the tool used, and report suggested references to be used with each tool. Most tools return results within minutes, but on large datasets runtimes for CIBERSORT can exceed hours or even days. We conclude that deconvolution methods are capable of returning high-quality results, but that proper reference selection is critical.
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http://dx.doi.org/10.1093/bib/bbab265DOI Listing
November 2021

Early adaptive chromatin remodeling events precede pathologic phenotypes and are reinforced in the failing heart.

J Mol Cell Cardiol 2021 11 15;160:73-86. Epub 2021 Jul 15.

Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine at UCLA, United States of America. Electronic address:

The temporal nature of chromatin structural changes underpinning pathologic transcription are poorly understood. We measured chromatin accessibility and DNA methylation to study the contribution of chromatin remodeling at different stages of cardiac hypertrophy and failure. ATAC-seq and reduced representation bisulfite sequencing were performed in cardiac myocytes after transverse aortic constriction (TAC) or depletion of the chromatin structural protein CTCF. Early compensation to pressure overload showed changes in chromatin accessibility and DNA methylation preferentially localized to intergenic and intronic regions. Most methylation and accessibility changes observed in enhancers and promoters at the late phase (3 weeks after TAC) were established at an earlier time point (3 days after TAC), before heart failure manifests. Enhancers were paired with genes based on chromatin conformation capture data: while enhancer accessibility generally correlated with changes in gene expression, this feature, nor DNA methylation, was alone sufficient to predict transcription of all enhancer interacting genes. Enrichment of transcription factors and active histone marks at these regions suggests that enhancer activity coordinates with other epigenetic factors to determine gene transcription. In support of this hypothesis, ChIP-qPCR demonstrated increased enhancer and promoter occupancy of GATA4 and NKX2.5 at Itga9 and Nppa, respectively, concomitant with increased transcription of these genes in the diseased heart. Lastly, we demonstrate that accessibility and DNA methylation are imperfect predictors of chromatin structure at the scale of A/B compartmentalization-rather, accessibility, DNA methylation, transcription factors and other histone marks work within these domains to determine gene expression. These studies establish that chromatin reorganization during early compensation after pathologic stimuli is maintained into the later decompensatory phases of heart failure. The findings reveal the rules for how local chromatin features govern gene expression in the context of global genomic structure and identify chromatin remodeling events for therapeutic targeting in disease.
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http://dx.doi.org/10.1016/j.yjmcc.2021.07.002DOI Listing
November 2021

The cellular architecture of the antimicrobial response network in human leprosy granulomas.

Nat Immunol 2021 07 24;22(7):839-850. Epub 2021 Jun 24.

Division of Dermatology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Granulomas are complex cellular structures composed predominantly of macrophages and lymphocytes that function to contain and kill invading pathogens. Here, we investigated the single-cell phenotypes associated with antimicrobial responses in human leprosy granulomas by applying single-cell and spatial sequencing to leprosy biopsy specimens. We focused on reversal reactions (RRs), a dynamic process whereby some patients with disseminated lepromatous leprosy (L-lep) transition toward self-limiting tuberculoid leprosy (T-lep), mounting effective antimicrobial responses. We identified a set of genes encoding proteins involved in antimicrobial responses that are differentially expressed in RR versus L-lep lesions and regulated by interferon-γ and interleukin-1β. By integrating the spatial coordinates of the key cell types and antimicrobial gene expression in RR and T-lep lesions, we constructed a map revealing the organized architecture of granulomas depicting compositional and functional layers by which macrophages, T cells, keratinocytes and fibroblasts can each contribute to the antimicrobial response.
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http://dx.doi.org/10.1038/s41590-021-00956-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579511PMC
July 2021

Targeting monoamine oxidase A-regulated tumor-associated macrophage polarization for cancer immunotherapy.

Nat Commun 2021 06 10;12(1):3530. Epub 2021 Jun 10.

Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, USA.

Targeting tumor-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumor microenvironment and improve cancer immunotherapy. Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain; small molecule MAO inhibitors (MAOIs) are clinically used for treating neurological disorders. Here we observe MAO-A induction in mouse and human TAMs. MAO-A-deficient mice exhibit decreased TAM immunosuppressive functions corresponding with enhanced antitumor immunity. MAOI treatment induces TAM reprogramming and suppresses tumor growth in preclinical mouse syngeneic and human xenograft tumor models. Combining MAOI and anti-PD-1 treatments results in synergistic tumor suppression. Clinical data correlation studies associate high intratumoral MAOA expression with poor patient survival in a broad range of cancers. We further demonstrate that MAO-A promotes TAM immunosuppressive polarization via upregulating oxidative stress. Together, these data identify MAO-A as a critical regulator of TAMs and support repurposing MAOIs for TAM reprogramming to improve cancer immunotherapy.
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http://dx.doi.org/10.1038/s41467-021-23164-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192781PMC
June 2021

Single Cell Transcriptomic Analyses Reveal the Impact of bHLH Factors on Human Retinal Organoid Development.

Front Cell Dev Biol 2021 13;9:653305. Epub 2021 May 13.

Department of Ophthalmology, Stein Eye Institute, University of California, Los Angeles, Los Angeles, CA, United States.

The developing retina expresses multiple bHLH transcription factors. Their precise functions and interactions in uncommitted retinal progenitors remain to be fully elucidated. Here, we investigate the roles of bHLH factors ATOH7 and Neurog2 in human ES cell-derived retinal organoids. Single cell transcriptome analyses identify three states of proliferating retinal progenitors: pre-neurogenic, neurogenic, and cell cycle-exiting progenitors. Each shows different expression profile of bHLH factors. The cell cycle-exiting progenitors feed into a postmitotic heterozygous neuroblast pool that gives rise to early born neuronal lineages. Elevating or expression accelerates the transition from the pre-neurogenic to the neurogenic state, and expands the exiting progenitor and neuroblast populations. In addition, ATOH7 and Neurog2 significantly, yet differentially, enhance retinal ganglion cell and cone photoreceptor production. Moreover, single cell transcriptome analyses reveal that ATOH7 and Neurog2 each assert positive autoregulation, and both suppress key bHLH factors associated with the pre-neurogenic and states and elevate bHLH factors expressed by exiting progenitors and differentiating neuroblasts. This study thus provides novel insight regarding how ATOH7 and Neurog2 impact human retinal progenitor behaviors and neuroblast fate choices.
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http://dx.doi.org/10.3389/fcell.2021.653305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155690PMC
May 2021

Targeting monoamine oxidase A for T cell-based cancer immunotherapy.

Sci Immunol 2021 May;6(59)

Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.

Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain, where it breaks down neurotransmitters and thereby influences mood and behavior. Small-molecule MAO inhibitors (MAOIs) have been developed and are clinically used for treating depression and other neurological disorders. However, the involvement of MAO-A in antitumor immunity has not been reported. Here, we observed induction of the gene in tumor-infiltrating immune cells. knockout mice exhibited enhanced antitumor T cell immunity and suppressed tumor growth. MAOI treatment significantly suppressed tumor growth in preclinical mouse syngeneic and human xenograft tumor models in a T cell-dependent manner. Combining MAOI and anti-PD-1 treatments generated synergistic tumor suppression effects. Clinical data correlation studies associated intratumoral expression with T cell dysfunction and decreased patient survival in a broad range of cancers. We further demonstrated that MAO-A restrains antitumor T cell immunity through controlling intratumoral T cell autocrine serotonin signaling. Together, these data identify MAO-A as an immune checkpoint and support repurposing MAOI antidepressants for cancer immunotherapy.
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http://dx.doi.org/10.1126/sciimmunol.abh2383DOI Listing
May 2021

BiSulfite Bolt: A bisulfite sequencing analysis platform.

Gigascience 2021 05;10(5)

Department of Molecular, Cell and Developmental Biology, University of California, 610 Charles E Young Dr S, Los Angeles, CA 90095, USA.

Background: Bisulfite sequencing is commonly used to measure DNA methylation. Processing bisulfite sequencing data is often challenging owing to the computational demands of mapping a low-complexity, asymmetrical library and the lack of a unified processing toolset to produce an analysis-ready methylation matrix from read alignments. To address these shortcomings, we have developed BiSulfite Bolt (BSBolt), a fast and scalable bisulfite sequencing analysis platform. BSBolt performs a pre-alignment sequencing read assessment step to improve efficiency when handling asymmetrical bisulfite sequencing libraries.

Findings: We evaluated BSBolt against simulated and real bisulfite sequencing libraries. We found that BSBolt provides accurate and fast bisulfite sequencing alignments and methylation calls. We also compared BSBolt to several existing bisulfite alignment tools and found BSBolt outperforms Bismark, BSSeeker2, BISCUIT, and BWA-Meth based on alignment accuracy and methylation calling accuracy.

Conclusion: BSBolt offers streamlined processing of bisulfite sequencing data through an integrated toolset that offers support for simulation, alignment, methylation calling, and data aggregation. BSBolt is implemented as a Python package and command line utility for flexibility when building informatics pipelines. BSBolt is available at https://github.com/NuttyLogic/BSBolt under an MIT license.
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http://dx.doi.org/10.1093/gigascience/giab033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106542PMC
May 2021

Genetically determined elevated C-reactive protein associated with primary colorectal cancer risk: Mendelian randomization with lifestyle interactions.

Am J Cancer Res 2021 15;11(4):1733-1753. Epub 2021 Apr 15.

Department of Epidemiology, Fielding School of Public Health, University of California Los Angeles, CA 90095, USA.

Systemic inflammation-related etiologic pathways via inflammatory cytokines in the development of colorectal cancer (CRC) have not been convincingly determined and may be confounded by lifestyle factors or reverse causality. We investigated the genetically predicted C-reactive protein (CRP) phenotype in the potential causal pathway of primary CRC risk in postmenopausal women in a Mendelian randomization (MR) framework. We employed individual-level data of the Women's Health Initiative Database for Genotypes and Phenotypes Study, which consists of 5 genome-wide association (GWA) studies, including 10,142 women, 737 of whom developed primary CRC. We examined 61 GWA single-nucleotide polymorphisms (SNPs) associated with CRP by using weighted/penalized MR weighted-medians and MR gene-environment interactions that allow some relaxation of the strict variable requirements and attenuate the heterogeneous estimates of outlying SNPs. In lifestyle-stratification analyses, genetically determined CRP exhibited its effects on the decreased CRC risk in non-viscerally obese and high-fat diet subgroups. In contrast, genetically driven CRP was associated with an increased risk for CRC in women who smoked ≥ 15 cigarettes/day, with significant interaction of the gene-smoking relationship. Further, a substantially increased risk of CRC induced by CRP was observed in relatively short-term users (< 5 years) of estrogen (E)-only and also longer-term users (5 to > 10 years) of E plus progestin. Our findings may provide novel evidence on immune-related etiologic pathways connected to CRC risk and suggest the possible use of CRP as a CRC-predictive biomarker in women with particular behaviors and CRP marker-informed interventions to reduce CRC risk.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085861PMC
April 2021

Single-cell sequencing of human white adipose tissue identifies new cell states in health and obesity.

Nat Immunol 2021 05 27;22(5):639-653. Epub 2021 Apr 27.

Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

White adipose tissue (WAT) is an essential regulator of energy storage and systemic metabolic homeostasis. Regulatory networks consisting of immune and structural cells are necessary to maintain WAT metabolism, which can become impaired during obesity in mammals. Using single-cell transcriptomics and flow cytometry, we unveil a large-scale comprehensive cellular census of the stromal vascular fraction of healthy lean and obese human WAT. We report new subsets and developmental trajectories of adipose-resident innate lymphoid cells, dendritic cells and monocyte-derived macrophage populations that accumulate in obese WAT. Analysis of cell-cell ligand-receptor interactions and obesity-enriched signaling pathways revealed a switch from immunoregulatory mechanisms in lean WAT to inflammatory networks in obese WAT. These results provide a detailed and unbiased cellular landscape of homeostatic and inflammatory circuits in healthy human WAT.
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http://dx.doi.org/10.1038/s41590-021-00922-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102391PMC
May 2021

GLUT1 overexpression enhances glucose metabolism and promotes neonatal heart regeneration.

Sci Rep 2021 04 21;11(1):8669. Epub 2021 Apr 21.

Department of Molecular, Cell, Developmental Biology, School of Life Science, University of California Los Angeles, Los Angeles, CA, USA.

The mammalian heart switches its main metabolic substrate from glucose to fatty acids shortly after birth. This metabolic switch coincides with the loss of regenerative capacity in the heart. However, it is unknown whether glucose metabolism regulates heart regeneration. Here, we report that glucose metabolism is a determinant of regenerative capacity in the neonatal mammalian heart. Cardiac-specific overexpression of Glut1, the embryonic form of constitutively active glucose transporter, resulted in an increase in glucose uptake and concomitant accumulation of glycogen storage in postnatal heart. Upon cryoinjury, Glut1 transgenic hearts showed higher regenerative capacity with less fibrosis than non-transgenic control hearts. Interestingly, flow cytometry analysis revealed two distinct populations of ventricular cardiomyocytes: Tnnt2-high and Tnnt2-low cardiomyocytes, the latter of which showed significantly higher mitotic activity in response to high intracellular glucose in Glut1 transgenic hearts. Metabolic profiling shows that Glut1-transgenic hearts have a significant increase in the glucose metabolites including nucleotides upon injury. Inhibition of the nucleotide biosynthesis abrogated the regenerative advantage of high intra-cardiomyocyte glucose level, suggesting that the glucose enhances the cardiomyocyte regeneration through the supply of nucleotides. Our data suggest that the increase in glucose metabolism promotes cardiac regeneration in neonatal mouse heart.
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http://dx.doi.org/10.1038/s41598-021-88159-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060418PMC
April 2021

IRAK2 Has a Critical Role in Promoting Feed-Forward Amplification of Epidermal Inflammatory Responses.

J Invest Dermatol 2021 10 15;141(10):2436-2448. Epub 2021 Apr 15.

Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA. Electronic address:

Many inflammatory skin diseases are characterized by altered epidermal differentiation. Whether this altered differentiation promotes inflammatory responses has been unknown. Here, we show that IRAK2, a member of the signaling complex downstream of IL-1 and IL-36, correlates positively with disease severity in both atopic dermatitis and psoriasis. Inhibition of epidermal IRAK2 normalizes differentiation and inflammation in two mouse models of psoriasis- and atopic dermatitis-like inflammation. Specifically, we demonstrate that IRAK2 ties together proinflammatory and differentiation-dependent responses and show that this function of IRAK2 is specific to keratinocytes and acts through the differentiation-associated transcription factor ZNF750. Taken together, our findings suggest that IRAK2 has a critical role in promoting feed-forward amplification of inflammatory responses in skin through modulation of differentiation pathways and inflammatory responses.
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http://dx.doi.org/10.1016/j.jid.2021.03.019DOI Listing
October 2021

Species-Specific Relationships between DNA and Chromatin Properties of CpG Islands in Embryonic Stem Cells and Differentiated Cells.

Stem Cell Reports 2021 Apr 25;16(4):899-912. Epub 2021 Mar 25.

Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA; Broad Stem Cell Research Center, University of California, Los Angeles, CA 90095, USA. Electronic address:

CpG islands often exhibit low DNA methylation, high histone H3 lysine 4 trimethylation, low nucleosome density, and high DNase I hypersensitivity, yet the rules by which CpG islands are sensed remain poorly understood. In this study, we first evaluated the relationships between the DNA and the chromatin properties of CpG islands in embryonic stem cells using modified bacterial artificial chromosomes. Then, using a bioinformatic approach, we identified strict CpG-island density and length thresholds in mouse embryonic stem and differentiated cells that consistently specify low DNA methylation levels. Surprisingly, the human genome exhibited a dramatically different relationship between DNA properties and DNA methylation levels of CpG islands. Further analysis allowed speculation that this difference is accommodated in part by evolutionary changes in the nucleotide composition of orthologous promoters. Thus, a change in the rules by which CpG-island properties are sensed may have co-evolved with compensatory genome adaptation events during mammalian evolution.
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http://dx.doi.org/10.1016/j.stemcr.2021.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072027PMC
April 2021

Human DNA methylation signatures differentiate persistent from resolving MRSA bacteremia.

Proc Natl Acad Sci U S A 2021 03;118(10)

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;

Persistent methicillin-resistant (MRSA) bacteremia is life threatening and occurs in up to 30% of MRSA bacteremia cases despite appropriate antimicrobial therapy. Isolates of MRSA that cause antibiotic-persistent methicillin-resistant bacteremia (APMB) typically have in vitro antibiotic susceptibilities equivalent to those causing antibiotic-resolving methicillin-resistant bacteremia (ARMB). Thus, persistence reflects host-pathogen interactions occurring uniquely in context of antibiotic therapy in vivo. However, host factors and mechanisms involved in APMB remain unclear. We compared DNA methylomes in circulating immune cells from patients experiencing APMB vs. ARMB. Overall, methylation signatures diverged in the distinct patient cohorts. Differentially methylated sites intensified proximate to transcription factor binding sites, primarily in enhancer regions. In APMB patients, significant hypomethylation was observed in binding sites for CCAAT enhancer binding protein-β (C/EBPβ) and signal transducer/activator of transcription 1 (STAT1). In contrast, hypomethylation in ARMB patients localized to glucocorticoid receptor and histone acetyltransferase p300 binding sites. These distinct methylation signatures were enriched in neutrophils and achieved a mean area under the curve of 0.85 when used to predict APMB using a classification model. These findings validated by targeted bisulfite sequencing (TBS-seq) differentiate epigenotypes in patients experiencing APMB vs. ARMB and suggest a risk stratification strategy for antibiotic persistence in patients treated for MRSA bacteremia.
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http://dx.doi.org/10.1073/pnas.2000663118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958259PMC
March 2021

Genetically Predicted C-Reactive Protein Associated With Postmenopausal Breast Cancer Risk: Interrelation With Estrogen and Cancer Molecular Subtypes Using Mendelian Randomization.

Front Oncol 2020 3;10:630994. Epub 2021 Feb 3.

Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, United States.

Background: Immune-related etiologic pathways that influence breast cancer risk are incompletely understood and may be confounded by lifestyles or reverse causality. Using a Mendelian randomization (MR) approach, we investigated the potential causal relationship between genetically elevated C-reactive protein (CRP) concentrations and primary invasive breast cancer risk in postmenopausal women.

Methods: We used individual-level data obtained from 10,179 women, including 537 who developed breast cancer, from the Women's Health Initiative Database for Genotypes and Phenotypes Study, which consists of five genome-wide association (GWA) studies. We examined 61 GWA single-nucleotide polymorphisms (SNPs) previously associated with CRP. We employed weighted/penalized weighted-medians and MR gene-environment interactions that allow instruments' invalidity to some extent and attenuate the heterogeneous estimates of outlying SNPs.

Results: In lifestyle-stratification analyses, genetically elevated CRP decreased risk for breast cancer in exogenous estrogen-only, estrogen + progestin, and past oral contraceptive (OC) users, but only among relatively short-term users (<5 years). Estrogen-only users for ≥5 years had more profound CRP-decreased breast cancer risk in dose-response fashion, whereas past OC users for ≥5 years had CRP-increased cancer risk. Also, genetically predicted CRP was strongly associated with increased risk for hormone-receptor positive or human epidermal growth factor receptor-2 negative breast cancer.

Conclusions: Our findings may provide novel evidence on the immune-related molecular pathways linking to breast cancer risk and suggest potential clinical use of CRP to predict the specific cancer subtypes. Our findings suggest potential interventions targeting CRP-inflammatory markers to reduce breast cancer risk.
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http://dx.doi.org/10.3389/fonc.2020.630994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888276PMC
February 2021

The Gene Expression Deconvolution Interactive Tool (GEDIT): accurate cell type quantification from gene expression data.

Gigascience 2021 02;10(2)

Bioinformatics Interdepartmental Degree Program, Molecular Biology Institute, Department of Molecular Cellular and Developmental Biology, and Institute for Genomics and Proteomics, University of California Los Angeles, 610 Charles E Young Dr S, Los Angeles, CA 90095, USA.

Background: The cell type composition of heterogeneous tissue samples can be a critical variable in both clinical and laboratory settings. However, current experimental methods of cell type quantification (e.g., cell flow cytometry) are costly, time consuming and have potential to introduce bias. Computational approaches that use expression data to infer cell type abundance offer an alternative solution. While these methods have gained popularity, most fail to produce accurate predictions for the full range of platforms currently used by researchers or for the wide variety of tissue types often studied.

Results: We present the Gene Expression Deconvolution Interactive Tool (GEDIT), a flexible tool that utilizes gene expression data to accurately predict cell type abundances. Using both simulated and experimental data, we extensively evaluate the performance of GEDIT and demonstrate that it returns robust results under a wide variety of conditions. These conditions include multiple platforms (microarray and RNA-seq), tissue types (blood and stromal), and species (human and mouse). Finally, we provide reference data from 8 sources spanning a broad range of stromal and hematopoietic types in both human and mouse. GEDIT also accepts user-submitted reference data, thus allowing the estimation of any cell type or subtype, provided that reference data are available.

Conclusions: GEDIT is a powerful method for evaluating the cell type composition of tissue samples and provides excellent accuracy and versatility compared to similar tools. The reference database provided here also allows users to obtain estimates for a wide variety of tissue samples without having to provide their own data.
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http://dx.doi.org/10.1093/gigascience/giab002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931818PMC
February 2021

Single-cell RNA sequencing of batch Chlamydomonas cultures reveals heterogeneity in their diurnal cycle phase.

Plant Cell 2021 05;33(4):1042-1057

Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, California 90095, USA.

The photosynthetic unicellular alga Chlamydomonas (Chlamydomonas reinhardtii) is a versatile reference for algal biology because of its ease of culture in the laboratory. Genomic and systems biology approaches have previously described transcriptome responses to environmental changes using bulk data, thus representing the average behavior from pools of cells. Here, we apply single-cell RNA sequencing (scRNA-seq) to probe the heterogeneity of Chlamydomonas cell populations under three environments and in two genotypes differing by the presence of a cell wall. First, we determined that RNA can be extracted from single algal cells with or without a cell wall, offering the possibility to sample natural algal communities. Second, scRNA-seq successfully separated single cells into nonoverlapping cell clusters according to their growth conditions. Cells exposed to iron or nitrogen deficiency were easily distinguished despite a shared tendency to arrest photosynthesis and cell division to economize resources. Notably, these groups of cells not only recapitulated known patterns observed with bulk RNA-seq but also revealed their inherent heterogeneity. A substantial source of variation between cells originated from their endogenous diurnal phase, although cultures were grown in constant light. We exploited this result to show that circadian iron responses may be conserved from algae to land plants. We document experimentally that bulk RNA-seq data represent an average of typically hidden heterogeneity in the population.
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http://dx.doi.org/10.1093/plcell/koab025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226295PMC
May 2021

Comparative analysis of embryo proper and suspensor transcriptomes in plant embryos with different morphologies.

Proc Natl Acad Sci U S A 2021 02;118(6)

Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095;

An important question is what genes govern the differentiation of plant embryos into suspensor and embryo proper regions following fertilization and division of the zygote. We compared embryo proper and suspensor transcriptomes of four plants that vary in embryo morphology within the suspensor region. We determined that genes encoding enzymes in several metabolic pathways leading to the formation of hormones, such as gibberellic acid, and other metabolites are up-regulated in giant scarlet runner bean and common bean suspensors. Genes involved in transport and Golgi body organization are up-regulated within the suspensors of these plants as well, strengthening the view that giant specialized suspensors serve as a hormone factory and a conduit for transferring substances to the developing embryo proper. By contrast, genes controlling transcriptional regulation, development, and cell division are up-regulated primarily within the embryo proper. Transcriptomes from less specialized soybean and suspensors demonstrated that fewer genes encoding metabolic enzymes and hormones are up-regulated. Genes active in the embryo proper, however, are functionally similar to those active in scarlet runner bean and common bean embryo proper regions. We uncovered a set of suspensor- and embryo proper-specific transcription factors (TFs) that are shared by all embryos irrespective of morphology, suggesting that they are involved in early differentiation processes common to all plants. Chromatin immunoprecipitation sequencing (ChIP-Seq) experiments with scarlet runner bean and soybean WOX9, an up-regulated suspensor TF, gained entry into a regulatory network important for suspensor development irrespective of morphology.
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http://dx.doi.org/10.1073/pnas.2024704118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017943PMC
February 2021

Integrative analysis of chloroplast DNA methylation in a marine alga-Saccharina japonica.

Plant Mol Biol 2021 Apr 2;105(6):611-623. Epub 2021 Feb 2.

Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, 266071, China.

Key Message: We applied an integrative approach using multiple methods to verify cytosine methylation in the chloroplast DNA of the multicellular brown alga Saccharina japonica. Cytosine DNA methylation is a heritable process which plays important roles in regulating development throughout the life cycle of an organism. Although methylation of nuclear DNA has been studied extensively, little is known about the state and role of DNA methylation in chloroplast genomes, especially in marine algae. Here, we have applied an integrated approach encompassing whole-genome bisulfite sequencing, methylated DNA immunoprecipitation, gene co-expression networks and photophysiological analyses to provide evidence for the role of chloroplast DNA methylation in a marine alga, the multicellular brown alga Saccharina japonica. Although the overall methylation level was relatively low in the chloroplast genome of S. japonica, gametophytes exhibited higher methylation levels than sporophytes. Gene-specific bisulfite-cloning sequencing provided additional evidence for the methylation of key photosynthetic genes. Many of them were highly expressed in sporophytes whereas genes involved in transcription, translation and biosynthesis were strongly expressed in gametophytes. Nucleus-encoded photosynthesis genes were co-expressed with their chloroplast-encoded counterparts potentially contributing to the higher photosynthetic performance in sporophytes compared to gametophytes where these co-expression networks were less pronounced. A nucleus-encoded DNA methyltransferase of the DNMT2 family is assumed to be responsible for the methylation of the chloroplast genome because it is predicted to possess a plastid transit peptide.
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http://dx.doi.org/10.1007/s11103-020-01113-9DOI Listing
April 2021

Pro-inflammatory cytokine polymorphisms and interactions with dietary alcohol and estrogen, risk factors for invasive breast cancer using a post genome-wide analysis for gene-gene and gene-lifestyle interaction.

Sci Rep 2021 01 13;11(1):1058. Epub 2021 Jan 13.

Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, 90095, USA.

Molecular and genetic immune-related pathways connected to breast cancer and lifestyles in postmenopausal women are not fully characterized. In this study, we explored the role of pro-inflammatory cytokines such as C-reactive protein (CRP) and interleukin-6 (IL-6) in those pathways at the genome-wide level. With single-nucleotide polymorphisms (SNPs) in the biomarkers and lifestyles together, we further constructed risk profiles to improve predictability for breast cancer. Our earlier genome-wide association gene-environment interaction study used large cohort data from the Women's Health Initiative Database for Genotypes and Phenotypes Study and identified 88 SNPs associated with CRP and IL-6. For this study, we added an additional 68 SNPs from previous GWA studies, and together with 48 selected lifestyles, evaluated for the association with breast cancer risk via a 2-stage multimodal random survival forest and generalized multifactor dimensionality reduction methods. Overall and in obesity strata (by body mass index, waist, waist-to-hip ratio, exercise, and dietary fat intake), we identified the most predictive genetic and lifestyle variables. Two SNPs (SALL1 rs10521222 and HLA-DQA1 rs9271608) and lifestyles, including alcohol intake, lifetime cumulative exposure to estrogen, and overall and visceral obesity, are the most common and strongest predictive markers for breast cancer across the analyses. The risk profile that combined those variables presented their synergistic effect on the increased breast cancer risk in a gene-lifestyle dose-dependent manner. Our study may contribute to improved predictability for breast cancer and suggest potential interventions for the women with the risk genotypes and lifestyles to reduce their breast cancer risk.
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http://dx.doi.org/10.1038/s41598-020-80197-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807068PMC
January 2021

Inhibition of microbiota-dependent TMAO production attenuates chronic kidney disease in mice.

Sci Rep 2021 01 12;11(1):518. Epub 2021 Jan 12.

Division of Cardiology, Department of Medicine, University of California, 10833 Le Conte Avenue, A2-237 CHS, Los Angeles, CA, 90095-1679, USA.

Patients with chronic kidney disease (CKD) have elevated circulating levels of trimethylamine N-oxide (TMAO), a metabolite derived from gut microbes and associated with cardiovascular diseases. High circulating levels of TMAO and its dietary precursor, choline, predict increased risk for development of CKD in apparently healthy subjects, and studies in mice fed TMAO or choline suggest that TMAO can contribute to kidney impairment and renal fibrosis. Here we examined the interactions between TMAO, kidney disease, and cardiovascular disease in mouse models. We observed that while female hyperlipidemic apoE KO mice fed a 0.2% adenine diet for 14 weeks developed CKD with elevated plasma levels of TMAO, provision of a non-lethal inhibitor of gut microbial trimethylamine (TMA) production, iodomethylcholine (IMC), significantly reduced multiple markers of renal injury (plasma creatinine, cystatin C, FGF23, and TMAO), reduced histopathologic evidence of fibrosis, and markedly attenuated development of microalbuminuria. In addition, while the adenine-induced CKD model significantly increased heart weight, a surrogate marker for myocardial hypertrophy, this was largely prevented by IMC supplementation. Surprisingly, adenine feeding did not increase atherosclerosis and significantly decreased the expression of inflammatory genes in the aorta compared to the control groups, effects unrelated to TMAO levels. Our data demonstrate that inhibition of TMAO production attenuated CKD development and cardiac hypertrophy in mice, suggesting that TMAO reduction may be a novel strategy in treating CKD and its cardiovascular disease complications.
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http://dx.doi.org/10.1038/s41598-020-80063-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804188PMC
January 2021
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