Publications by authors named "Jeong-Heon Lee"

118 Publications

Epigenetic alteration contributes to the transcriptional reprogramming in T-cell prolymphocytic leukemia.

Sci Rep 2021 Apr 15;11(1):8318. Epub 2021 Apr 15.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

T cell prolymphocytic leukemia (T-PLL) is a rare disease with aggressive clinical course. Cytogenetic analysis, whole-exome and whole-genome sequencing have identified primary structural alterations in T-PLL, including inversion, translocation and copy number variation. Recurrent somatic mutations were also identified in genes encoding chromatin regulators and those in the JAK-STAT signaling pathway. Epigenetic alterations are the hallmark of many cancers. However, genome-wide epigenomic profiles have not been reported in T-PLL, limiting the mechanistic study of its carcinogenesis. We hypothesize epigenetic mechanisms also play a key role in T-PLL pathogenesis. To systematically test this hypothesis, we generated genome-wide maps of regulatory regions using H3K4me3 and H3K27ac ChIP-seq, as well as RNA-seq data in both T-PLL patients and healthy individuals. We found that genes down-regulated in T-PLL are mainly associated with defense response, immune system or adaptive immune response, while up-regulated genes are enriched in developmental process, as well as WNT signaling pathway with crucial roles in cell fate decision. In particular, our analysis revealed a global alteration of regulatory landscape in T-PLL, with differential peaks highly enriched for binding motifs of immune related transcription factors, supporting the epigenetic regulation of oncogenes and genes involved in DNA damage response and T-cell activation. Together, our work reveals a causal role of epigenetic dysregulation in T-PLL.
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http://dx.doi.org/10.1038/s41598-021-87890-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050249PMC
April 2021

ZNF416 is a pivotal transcriptional regulator of fibroblast mechanoactivation.

J Cell Biol 2021 May;220(5)

Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN.

Matrix stiffness is a central regulator of fibroblast function. However, the transcriptional mechanisms linking matrix stiffness to changes in fibroblast phenotype are incompletely understood. Here, we evaluated the effect of matrix stiffness on genome-wide chromatin accessibility in freshly isolated lung fibroblasts using ATAC-seq. We found higher matrix stiffness profoundly increased global chromatin accessibility relative to lower matrix stiffness, and these alterations were in close genomic proximity to known profibrotic gene programs. Motif analysis of these regulated genomic loci identified ZNF416 as a putative mediator of fibroblast stiffness responses. Genome occupancy analysis using ChIP-seq confirmed that ZNF416 occupies a broad range of genes implicated in fibroblast activation and tissue fibrosis, with relatively little overlap in genomic occupancy with other mechanoresponsive and profibrotic transcriptional regulators. Using loss- and gain-of-function studies, we demonstrated that ZNF416 plays a critical role in fibroblast proliferation, extracellular matrix synthesis, and contractile function. Together, these observations identify ZNF416 as novel mechano-activated transcriptional regulator of fibroblast biology.
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http://dx.doi.org/10.1083/jcb.202007152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918622PMC
May 2021

Establishment of an Acanthamoeba keratitis mouse model confirmed by amoebic DNA amplification.

Sci Rep 2021 Feb 18;11(1):4183. Epub 2021 Feb 18.

Department of Microbiology, Ajou University School of Medicine, Suwon, 16499, Republic of Korea.

Acanthamoeba castellanii, the causative agent of Acanthamoeba keratitis (AK), occurs mainly in contact lens users with poor eye hygiene. The findings of many in vitro studies of AK, as well as the testing of therapeutic drugs, need validation in in vivo experiments. BALB/c mice were used in this study to establish in vivo AK model. A. castellanii cell suspensions (equal mixtures of trophozoites and cysts) were loaded onto 2-mm contact lens pieces and inserted into mouse eyes that were scratched using an ophthalmic surgical blade under anesthesia and the eyelids of the mice were sutured. The AK signs were grossly observed and PCR was performed using P-FLA primers to amplify the Acanthamoeba 18S-rRNA gene from mouse ocular tissue. The experimental AK mouse model was characterized by typical hazy blurring and melting of the mouse cornea established on day 1 post-inoculation. AK was induced with at least 0.3 × 10 A. castellanii cells (optimal number, 5 × 10), and the infection persisted for two months. The PCR products amplified from the extracted mouse eye DNA confirmed the development of Acanthamoeba-induced keratitis during the infection periods. In conclusion, the present AK mouse model may serve as an important in vivo model for the development of various therapeutic drugs against AK.
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http://dx.doi.org/10.1038/s41598-021-83738-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892866PMC
February 2021

Lipid-induced endothelial vascular cell adhesion molecule 1 promotes nonalcoholic steatohepatitis pathogenesis.

J Clin Invest 2021 Mar;131(6)

Division of Gastroenterology and Hepatology.

Monocyte homing to the liver and adhesion to the liver sinusoidal endothelial cells (LSECs) are key elements in nonalcoholic steatohepatitis (NASH) pathogenesis. We reported previously that VCAM-1 mediates monocyte adhesion to LSECs. However, the pathogenic role of VCAM-1 in NASH is unclear. Herein, we report that VCAM-1 was a top upregulated adhesion molecule in the NASH mouse liver transcriptome. Open chromatin landscape profiling combined with genome-wide transcriptome analysis showed robust transcriptional upregulation of LSEC VCAM-1 in murine NASH. Moreover, LSEC VCAM-1 expression was significantly increased in human NASH. LSEC VCAM-1 expression was upregulated by palmitate treatment in vitro and reduced with inhibition of the mitogen-activated protein 3 kinase (MAP3K) mixed lineage kinase 3 (MLK3). Likewise, LSEC VCAM-1 expression was reduced in the Mlk3-/- mice with diet-induced NASH. Furthermore, VCAM-1 neutralizing Ab or pharmacological inhibition attenuated diet-induced NASH in mice, mainly via reducing the proinflammatory monocyte hepatic population as examined by mass cytometry by time of flight (CyTOF). Moreover, endothelium-specific Vcam1 knockout mice were also protected against NASH. In summary, lipotoxic stress enhances the expression of LSEC VCAM-1, in part, through MLK3 signaling. Inhibition of VCAM-1 was salutary in murine NASH and might serve as a potential therapeutic strategy for human NASH.
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http://dx.doi.org/10.1172/JCI143690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954604PMC
March 2021

Genomic and Epigenomic Landscaping Defines New Therapeutic Targets for Adenosquamous Carcinoma of the Pancreas.

Cancer Res 2020 10 14;80(20):4324-4334. Epub 2020 Sep 14.

Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona.

Adenosquamous cancer of the pancreas (ASCP) is a subtype of pancreatic cancer that has a worse prognosis and greater metastatic potential than the more common pancreatic ductal adenocarcinoma (PDAC) subtype. To distinguish the genomic landscape of ASCP and identify actionable targets for this lethal cancer, we applied DNA content flow cytometry to a series of 15 tumor samples including five patient-derived xenografts (PDX). We interrogated purified sorted tumor fractions from these samples with whole-genome copy-number variant (CNV), whole-exome sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analyses. These identified a variety of somatic genomic lesions targeting chromatin regulators in ASCP genomes that were superimposed on well-characterized genomic lesions including mutations in (87%) and (73%), amplification of (47%), and homozygous deletion of (40%) that are common in PDACs. Furthermore, a comparison of ATAC-seq profiles of three ASCP and three PDAC genomes using flow-sorted PDX models identified genes with accessible chromatin unique to the ASCP genomes, including the lysine methyltransferase and the pancreatic cancer stem cell regulator in all three ASCPs, and a fusion associated with focal CNVs in both genes in a single ASCP. Finally, we demonstrate significant activity of a pan FGFR inhibitor against organoids derived from the fusion-positive ASCP PDX model. Our results suggest that the genomic and epigenomic landscape of ASCP provide new strategies for targeting this aggressive subtype of pancreatic cancer. SIGNIFICANCE: These data provide a unique description of the ASCP genomic and epigenomic landscape and identify candidate therapeutic targets for this dismal cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906529PMC
October 2020

Chronic lymphocytic leukemia (CLL) risk is mediated by multiple enhancer variants within CLL risk loci.

Hum Mol Genet 2020 09;29(16):2761-2774

Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries. It has a strong genetic basis, showing a ~ 8-fold increased risk of CLL in first-degree relatives. Genome-wide association studies (GWAS) have identified 41 risk variants across 41 loci. However, for a majority of the loci, the functional variants and the mechanisms underlying their causal roles remain undefined. Here, we examined the genetic and epigenetic features associated with 12 index variants, along with any correlated (r2 ≥ 0.5) variants, at the CLL risk loci located outside of gene promoters. Based on publicly available ChIP-seq and chromatin accessibility data as well as our own ChIP-seq data from CLL patients, we identified six candidate functional variants at six loci and at least two candidate functional variants at each of the remaining six loci. The functional variants are predominantly located within enhancers or super-enhancers, including bi-directionally transcribed enhancers, which are often restricted to immune cell types. Furthermore, we found that, at 78% of the functional variants, the alternative alleles altered the transcription factor binding motifs or histone modifications, indicating the involvement of these variants in the change of local chromatin state. Finally, the enhancers carrying functional variants physically interacted with genes enriched in the type I interferon signaling pathway, apoptosis, or TP53 network that are known to play key roles in CLL. These results support the regulatory roles for inherited noncoding variants in the pathogenesis of CLL.
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http://dx.doi.org/10.1093/hmg/ddaa165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530532PMC
September 2020

H2B ubiquitylation enhances H3K4 methylation activities of human KMT2 family complexes.

Nucleic Acids Res 2020 06;48(10):5442-5456

Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, South Korea.

In mammalian cells, distinct H3K4 methylation states are created by deposition of methyl groups by multiple complexes of histone lysine methyltransferase 2 (KMT2) family proteins. For comprehensive analyses that directly compare the catalytic properties of all six human KMT2 complexes, we employed a biochemically defined system reconstituted with recombinant KMT2 core complexes (KMT2CoreCs) containing minimal components required for nucleosomal H3K4 methylation activity. We found that each KMT2CoreC generates distinct states and different levels of H3K4 methylation, and except for MLL3 all are stimulated by H2Bub. Notably, SET1BCoreC exhibited the strongest H3K4 methylation activity and, to our surprise, did not require H2B ubiquitylation (H2Bub); in contrast, H2Bub was required for the H3K4me2/3 activity of the paralog SET1ACoreC. We also found that WDR5, RbBP5, ASH2L and DPY30 are required for efficient H3K4 methyltransferase activities of all KMT2CoreCs except MLL3, which could produce H3K4me1 in the absence of WDR5. Importantly, deletion of the PHD2 domain of CFP1 led to complete loss of the H3K4me2/3 activities of SET1A/BCoreCs in the presence of H2Bub, indicating a critical role for this domain in the H2Bub-stimulated H3K4 methylation. Collectively, our results suggest that each KMT2 complex methylates H3K4 through distinct mechanisms in which individual subunits differentially participate.
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http://dx.doi.org/10.1093/nar/gkaa317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261165PMC
June 2020

Epigenetic Alterations Are Associated With Gastric Emptying Disturbances in Diabetes Mellitus.

Clin Transl Gastroenterol 2020 03;11(3):e00136

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.

Introduction: Epigenetic modifications have been implicated to mediate several complications of diabetes mellitus (DM), especially nephropathy and retinopathy. Our aim was to ascertain whether epigenetic alterations in whole blood discriminate among patients with DM with normal, delayed, and rapid gastric emptying (GE).

Methods: Using the ChIP-seq (chromatin immunoprecipitation combined with next-generation sequencing) assays, we compared the genome-wide enrichment of 3 histone modifications (i.e., H3K4me3, H3K9ac, and H3K27ac) in buffy coats from 20 diabetic patients with gastrointestinal symptoms and normal (n = 6), delayed (n = 8), or rapid (n = 6) GE.

Results: Between patients with DM with delayed vs normal GE, there were 108 and 54 genes that were differentially bound (false discovery rate < 0.05) with H3K27ac and H3K9ac, respectively; 100 genes were differentially bound with H3K9ac in patients with rapid vs normal GE. The differentially bound genes with H3K27ac were functionally linked to the type 2 immune response, particularly Th2 cell activation and function (e.g., CCR3, CRLF2, CXCR4, IL5RA, and IL1RL1) and glucose homeostasis (FBP-1, PDE4A, and CMKLR1). For H3K9ac, the differentially occupied genes were related to T-cell development and function (e.g., ICOS and CCR3) and innate immunity (RELB, CD300LB, and CLEC2D). Compared with normal GE, rapid GE had differential H3K9ac peaks at the promoter site of diverse immunity-related genes (e.g., TNFRSF25 and CXCR4) and genes related to insulin resistance and glucose metabolism. Motif analysis disclosed enrichment of binding sites for transcription factors relevant to the pathogenesis and complications of DM.

Discussion: GE disturbances in DM are associated with epigenetic alterations that pertain to dysimmunity, glucose metabolism, and other complications of DM.
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http://dx.doi.org/10.14309/ctg.0000000000000136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145053PMC
March 2020

Chemical Modulation of Bioengineered Exosomes for Tissue-Specific Biodistribution.

Adv Ther (Weinh) 2019 Nov 13;2(11). Epub 2019 Sep 13.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

The physicochemical properties of nanomaterials play a key role in tissue-specific targeting by reducing nonspecific background uptake as well as controlling biodistribution and clearance. Due to the strong influence of surface chemistry, chemical modulation of bioinert exosomes with chargeable and traceable small molecule fluorophores has a significant effect on the targeting, stability, and toxicity of the final conjugates. In this study, charge-variable exosomes are designed by conjugating their surface proteins with near-infrared fluorophores to control the in vivo fate of exosomes. Interestingly, zwitterionic fluorophore-labeled exosomes show rapid renal clearance with minimum to none nonspecific tissue uptake, whereas anionic exosomes are excreted through the hepatobiliary route with high uptake in the liver. The biodistribution and pharmacokinetics of exosome conjugates are comparable to their corresponding free fluorophores, demonstrating that the surface characteristics govern the fate of final conjugates in the living organism. Such unique surface properties of chemically modulated exosomes are confirmed in the lymphatic system after intradermal administration, which results in distinctive kinetic profiles in the secondary lymphoid tissues. This finding can subsequently serve as the foundation for developing tissue-specific exosome-based therapeutics.
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http://dx.doi.org/10.1002/adtp.201900111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172497PMC
November 2019

Rapid and Selective Targeting of Heterogeneous Pancreatic Neuroendocrine Tumors.

iScience 2020 Apr 25;23(4):101006. Epub 2020 Mar 25.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address:

Design of tissue-specific contrast agents to delineate tumors from background tissues is a major unmet clinical need for ultimate surgical interventions. Bioconjugation of fluorophore(s) to a ligand has been mainly used to target overexpressed receptors on tumors. However, the size of the final targeted ligand can be large, >20 kDa, and cannot readily cross the microvasculature to meet the specific tissue, resulting in low targetability with a high background. Here, we report a small and hydrophilic phenoxazine with high targetability and retention to pancreatic neuroendocrine tumor. This bioengineered fluorophore permits sensitive detection of ultrasmall (<0.5 mm) ectopic tumors within a few seconds after a single bolus injection, highlighting every tumor in the pancreas from the surrounding healthy tissues with reasonable half-life. The knowledge-based approach and validation used to develop structure-inherent tumor-targeted fluorophores have a tremendous potential to improve treatment outcome by providing definite tumor margins for image-guided surgery.
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http://dx.doi.org/10.1016/j.isci.2020.101006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139119PMC
April 2020

Highly Stable and Flexible Memristive Devices Based on Polyvinylpyrrolidone: WS Quantum Dots.

Sci Rep 2020 Apr 1;10(1):5793. Epub 2020 Apr 1.

Department of Electronic and Computer Engineering, Hanyang University, Seoul, 133-791, South Korea.

Tungsten disulfide (WS) quantum dots (QDs) embedded in polyvinylpyrrolidone (PVP) based flexible memristive devices were prepared, and those devices exhibited typical bistable electrical switching and remarkable nonvolatile memristive behaviors. Maximum electricity ON/OFF ratio obtained from the current-voltage (I-V) curves of the device is close to 10. The set voltage of the device is +0.7 V, which effectively reduced the energy consumption. The retention times extracted from data for the devices were as large as 1 × 10 s, which points to these devices having nonvolatile characteristics. Moreover, the highly flexible characteristics of the devices were demonstrated by bending the devices. The carrier transport mechanisms were explained by fitting the I-V curves, and possible operating mechanisms of the devices can be described based on the electron trapping and detrapping processes. WS QDs uniformly dispersed in pure transparent N, N-Dimethylformamide (DMF) were obtained by using ultrasonication and a hydrothermal process in this work.
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http://dx.doi.org/10.1038/s41598-020-62721-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113290PMC
April 2020

Fluorometric Imaging for Early Diagnosis and Prognosis of Rheumatoid Arthritis.

Adv Sci (Weinh) 2020 Jan 1;7(1):1902267. Epub 2019 Dec 1.

Gordon Center for Medical Imaging Department of Radiology Massachusetts General Hospital and Harvard Medical School Boston MA 02114 USA.

Early diagnosis and monitoring of disease progress are of significant importance in the effective treatment of rheumatoid arthritis (RA), because the continuing inflammation can lead to irreversible joint damage and systemic complications. However, applying imaging modalities for the prognosis of RA remains challenging, because no tissue-specific guidelines are available to monitor the progressive course of RA. In this study, fluorometric imaging of RA is reported using bioengineered targeted agents of the blood vessel, bone, and cartilage in combination with the customized optical fluorescence imaging system. Separate but simultaneous tissue-specific images of synovitis, cartilage destruction, and bone resorption are obtained from a mouse model of RA, which allows quantification of the prognosis of diseases at each stage. Thus, the fluorometric imaging of RA by using tissue-specific contrast agents plays a key role in the systemic treatment of RA by monitoring structural damage and disease progression.
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http://dx.doi.org/10.1002/advs.201902267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947695PMC
January 2020

Highly flexible and stable resistive switching devices based on WS nanosheets:poly(methylmethacrylate) nanocomposites.

Sci Rep 2019 Dec 17;9(1):19316. Epub 2019 Dec 17.

Department of Electronics and Computer Engineering, Hanyang University, Seoul, 04763, Republic of Korea.

This paper reports data for the electrical characteristics and the operating mechanisms of flexible resistive switching devices based on WS nanosheets (NSs) dispersed in a poly(methyl methacrylate) (PMMA) layer. The ON/OFF ratio of the memristive device based on an Al/WS NSs:PMMA/indium tin oxides (ITO) structure was approximately 5.9 × 10. The memristive device based on the WS NSs also exhibited the bipolar switching characteristics with low power consumption and great performance in the bent state with radii of the curvatures of 20 and 10 mm. Especially, the results obtained after bending the device were similar to those observed before bending. The device showed nearly the same ON/OFF ratio for a retention time of 1 × 10 sec, and the number of endurance cycles was greater than 1 × 10. The set voltage and the reset voltage probability distributions for the setting and the resetting processes indicated bipolar switching characteristics. The operating and the carrier transport mechanisms of the Al/WS NSs:PMMA/ITO device could be explained based on the current-voltage results with the aid of an energy band diagram.
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http://dx.doi.org/10.1038/s41598-019-55637-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917699PMC
December 2019

Umbelliferone reduces the expression of inflammatory chemokines in HaCaT cells and DNCB/DFE-induced atopic dermatitis symptoms in mice.

Int Immunopharmacol 2019 Oct 19;75:105830. Epub 2019 Aug 19.

Department of Immunology and Institute of Medical Sciences, Medical School, Chonbuk National University, Jeonju, Jeonbuk 54907, Republic of Korea. Electronic address:

Umbelliferone (UMB) is a coumarin derivative present in roots and barks of plants, such as Angelica decursiva, Artemisia capillaris, and orange. UMB has been previously reported to exhibit anti-inflammatory, anti-diabetic, and anti-cancer effects. However, the effect of UMB on atopic dermatitis (AD) remains unknown. The purpose of this study was to investigate the anti-atopic effects of UMB on 2,4-dinitrochlorobenzene (DNCB)- and house dust mite extract (Dermatophagoides farinae extract, DFE)-treated mice with AD-like skin lesions and on tumor necrosis factor (TNF)-α/interferon (IFN)-γ-treated HaCaT cells. In DNCB/DFE-treated mice, oral administration of UMB (20 and 40 mg/kg) for 28 days led to a significant decrease in ear thickness, spleen size and weight, serum levels of immunoglobulin E (IgE), IgG1, IgG2a, TNF-α, and interleukin 4 (IL-4), and mast cell infiltration; it also led to the suppression of pro-inflammatory cytokines and chemokines. In addition, UMB reduced the secretion of pro-inflammatory cytokines and chemokines in TNF-α/IFN-γ-treated HaCaT cells via regulation of MAPK, IkB-α/NF-κB, and STAT1 signaling pathways. Taken together, these results indicate that UMB ameliorates AD-associated symptoms and inflammation via regulation of various signaling pathways, suggesting that UMB might be a potential therapeutic agent of AD.
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http://dx.doi.org/10.1016/j.intimp.2019.105830DOI Listing
October 2019

Single Nucleotide Polymorphisms at a Distance from Aryl Hydrocarbon Receptor (AHR) Binding Sites Influence AHR Ligand-Dependent Gene Expression.

Drug Metab Dispos 2019 09 10;47(9):983-994. Epub 2019 Jul 10.

Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics (D.R.N., D.L., H.L., L.W., R.M.W.), Epigenomics Program, Center for Individualized Medicine (J.-H.L., T.O.), Division of Experimental Pathology and Laboratory Medicine, Department of Laboratory Medicine and Pathology (J.-H.L.), Division of Biomedical Statistics and Informatics (Z.Y.), Department of Physiology and Biomedical Engineering (T.O.), and Division of Gastroenterology and Hepatology, Department of Medicine (T.O.), Mayo Clinic, Rochester, Minnesota

Greater than 90% of significant genome-wide association study (GWAS) single-nucleotide polymorphisms (SNPs) are in noncoding regions of the genome, but only 25.6% are known expression quantitative trait loci (eQTLs). Therefore, the function of many significant GWAS SNPs remains unclear. We have identified a novel type of eQTL for which SNPs distant from ligand-activated transcription factor (TF) binding sites can alter target gene expression in a SNP genotype-by-ligand-dependent fashion that we refer to as pharmacogenomic eQTLs (PGx-eQTLs)-loci that may have important pharmacotherapeutic implications. In the present study, we integrated chromatin immunoprecipitation-seq with RNA-seq and SNP genotype data for a panel of lymphoblastoid cell lines to identify 10 novel PGx-eQTLs dependent on the ligand-activated TF aryl hydrocarbon receptor (AHR)-a critical environmental sensor for xenobiotic (drug) and immune response. Those 10 PGx-eQTLs were eQTLs only after AHR ligand treatment, even though the SNPs did not create/destroy an AHR response element-the DNA sequence motif recognized and bound by AHR. Additional functional studies in multiple cell lines demonstrated that some PGx-eQTLs are functional in multiple cell types, whereas others displayed SNP-by-ligand-dependent effects in just one cell type. Furthermore, four of those PGx-eQTLs had previously been associated with clinical phenotypes, indicating that those loci might have the potential to inform clinical decisions. Therefore, SNPs across the genome that are distant from TF binding sites for ligand-activated TFs might function as PGx-eQTLs and, as a result, might have important clinical implications for interindividual variation in drug response. SIGNIFICANCE STATEMENT: More than 90% of single-nucleotide polymorphisms (SNPs) that are associated with clinical phenotypes are located in noncoding regions of the genome. However, the mechanisms of action of many of those SNPs have not been elucidated, and drugs may unmask functional expression quantitative trail loci (eQTLs). In the current study, we used drugs that bind to the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and identified SNPs that were associated with interindividual variation in gene expression following drug exposure-termed pharmacogenomic (PGx)-eQTLs. Possibly of greater significance, those PGx-eQTL SNPs were outside of AHR binding sites, indicating that they do not interrupt AHR DNA recognition. PGx-eQTLs such as those described in this work may have crucial implications for interindividual variation in drug.
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http://dx.doi.org/10.1124/dmd.119.087312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184190PMC
September 2019

Recurrent mutations in ALK-negative anaplastic large cell lymphoma.

Blood 2019 06 17;133(26):2776-2789. Epub 2019 May 17.

Division of Hematology, Mayo Clinic, Rochester, MN.

Anaplastic large cell lymphomas (ALCLs) represent a relatively common group of T-cell non-Hodgkin lymphomas (T-NHLs) that are unified by similar pathologic features but demonstrate marked genetic heterogeneity. ALCLs are broadly classified as being anaplastic lymphoma kinase (ALK) or ALK, based on the presence or absence of rearrangements. Exome sequencing of 62 T-NHLs identified a previously unreported recurrent mutation in the musculin gene, , exclusively in ALK ALCLs. Additional sequencing for a total of 238 T-NHLs confirmed the specificity of for ALK ALCL and further demonstrated that 14 of 15 mutated cases (93%) had coexisting rearrangements. Musculin is a basic helix-loop-helix (bHLH) transcription factor that heterodimerizes with other bHLH proteins to regulate lymphocyte development. The E116K mutation localized to the DNA binding domain of musculin and permitted formation of musculin-bHLH heterodimers but prevented their binding to authentic target sequence. Functional analysis showed MSC acted in a dominant-negative fashion, reversing wild-type musculin-induced repression of and cell cycle inhibition. Chromatin immunoprecipitation-sequencing and transcriptome analysis identified the cell cycle regulatory gene as a direct transcriptional target of musculin. MSC reversed E2F2-induced cell cycle arrest and promoted expression of the CD30-IRF4-MYC axis, whereas its expression was reciprocally induced by binding of IRF4 to the promoter. Finally, ALCL cells expressing were preferentially targeted by the BET inhibitor JQ1. These findings identify a novel recurrent mutation as a key driver of the CD30-IRF4-MYC axis and cell cycle progression in a unique subset of ALCLs.
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http://dx.doi.org/10.1182/blood.2019000626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598380PMC
June 2019

Enhanced and controlled chromatin extraction from FFPE tissues and the application to ChIP-seq.

BMC Genomics 2019 Mar 29;20(1):249. Epub 2019 Mar 29.

Epigenomics Development Laboratory, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Stabile building 12-04, 200 First Street SW, Rochester, MN, 55905, USA.

Background: Epigenetic dysregulation is involved in the etiology and progression of various human diseases. Formalin-fixed paraffin-embedded (FFPE) samples represent the gold standard for archiving pathology samples, and thus FFPE samples are a major resource of samples in clinical research. However, chromatin-based epigenetic assays in the clinical settings are limited to fresh or frozen samples, and are hampered by low chromatin yield in FFPE samples due to the lack of a reliable and efficient chromatin preparation method. Here, we introduce a new chromatin extraction method from FFPE tissues (Chrom-EX PE) for chromatin-based epigenetic assays.

Results: During rehydration of FFPE tissues, applying a tissue-level cross-link reversal into the deparaffinized tissue at 65 °C dramatically increased chromatin yield in the soluble fraction. The resulting chromatin is compatible with targeted ChIP-qPCR and genome-wide ChIP-seq approaches. The chromatin prepared by Chrom-EX PE showed a gradual fragmentation pattern with varying incubation temperature. At temperatures below 37 °C, the majority of soluble chromatin is over 1 kb. The soluble chromatin prepared in the range of 45-60 °C showed a typical nucleosomal pattern. And the majority of chromatin prepared at 65 °C is close to mononucleosomal size. These observations indicate that chromatin preparation from FFPE samples can be controlled for downstream chromatin-based epigenetic assays.

Conclusions: This study provided a new method that achieves efficient extraction of high-quality chromatin suitable for chromatin-based epigenetic assays with less damage on chromatin. This approach may provide a way to circumvent the over-fixed nature of FFPE tissues for future technology development.
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http://dx.doi.org/10.1186/s12864-019-5639-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440302PMC
March 2019

An Extremely Inexpensive, Simple, and Flexible Carbon Fiber Electrode for Tunable Elastomeric Piezo-Resistive Sensors and Devices Realized by LSTM RNN.

ACS Appl Mater Interfaces 2019 Mar 15;11(12):11910-11919. Epub 2019 Mar 15.

Here, we describe the utility of a carbon fiber (CF) electrode that is inexpensive, simple, and flexible and can be embedded with elastomeric nanocomposite piezo-resistive sensors fabricated from silicone rubber (Ecoflex) blended with carbon nanotubes (CNTs) and various wt % of silicone thinner to tune the sensitivity and softness range. The performance of the CF electrode was evaluated on the basis of piezo-resistive responses from the sensors subjected to dynamic sinusoidal compressive strains at different levels and frequencies. The responses were positive-pressure effects with rate-dependent asymmetric nonlinear hysteresis characteristics. Developing a mathematical model to describe the rate-dependent asymmetric nonlinear hysteresis behavior is technically impossible; therefore, we employed artificial intelligence-based hysteresis modeling, long short-term memory recurrent neural network, to describe the hysteresis nonlinearity. The debonding strength of the CF electrode was determined in the pull-off testing and was found to be much higher than that of a copper wire electrode. The debonding mechanism was further elucidated via an in situ resistance profile. The importance of a robust conductive interface between a CF electrode and a nanocomposite was experimentally demonstrated. It was found that the inherent piezo-resistance of the CF was negligible compared with the piezo-resistance of the sensor; therefore, the signals from the sensor were free of interference. We believe CF-embedded tunable piezo-resistive sensors could be used in biomedical devices, artificial e-skins, robotic touch applications, and flexible keyboards where the required stretchability of the electrode can be introduced via an appropriate geometrical design.
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http://dx.doi.org/10.1021/acsami.9b00464DOI Listing
March 2019

Lysosome-Targeted Bioprobes for Sequential Cell Tracking from Macroscopic to Microscopic Scales.

Adv Mater 2019 Apr 10;31(14):e1806216. Epub 2019 Feb 10.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.

Longitudinal tracking of living cells is crucial to understanding the mechanism of action and toxicity of cell-based therapeutics. To quantify the presence of administered cells in the host tissue without sacrifice of animals, labeling of the target cells with a nontoxic and stable contrast agent is a prerequisite. However, such long-term live cell tracking is currently limited by the lack of fluorophores with steady optical and physicochemical properties in the near-infrared (NIR) window. Herein, for the first time, the design of fixable cell-tracking NIR fluorophores (CTNFs) with high optical properties, excellent cell permeation and retention, and high stability against chemical treatments is reported. Efficient cellular labeling and tracking of CTNFs using intraoperative optical fluorescence imaging by following the fate of NIR-labeled cells from the time of injection into animals to ex vivo cellular analysis after resection of the target tissue is demonstrated. Due to the lipophilic cationicity and primary amine docking group, CTNF126 outperforms the other tested fluorophores with rapid diffusion into the cytoplasmic membrane and sequestration inside the lysosomes, which prevents cellular efflux and improves cellular retention. Thus, CTNF126 will be useful to track cells in living organisms for the mechanism of action at the single cell level.
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http://dx.doi.org/10.1002/adma.201806216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6574216PMC
April 2019

HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4CD8 thymocytes for CD4-lineage commitment.

Elife 2019 01 18;8. Epub 2019 Jan 18.

Department of Immunology, Mayo Clinic, Rochester, United States.

CD4 and CD8 T cells are vital components of the immune system. We found that histone deacetylase 3 (HDAC3) is critical for the development of CD4 T cells, as HDAC3-deficient DP thymocytes generate only CD8SP thymocytes in mice. In the absence of HDAC3, MHC Class II-restricted OT-II thymocytes are redirected to the CD8 cytotoxic lineage, which occurs with accelerated kinetics. Analysis of histone acetylation and RNA-seq reveals that HDAC3-deficient DP thymocytes are biased towards the CD8 lineage prior to positive selection. Commitment to the CD4 or CD8 lineage is determined by whether persistent TCR signaling or cytokine signaling predominates, respectively. Despite elevated IL-21R/γc/STAT5 signaling in HDAC3-deficient DP thymocytes, blocking IL-21R does not restore CD4 lineage commitment. Instead, HDAC3 binds directly to CD8-lineage promoting genes. Thus, HDAC3 is required to restrain CD8-lineage genes in DP thymocytes for the generation of CD4 T cells.
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http://dx.doi.org/10.7554/eLife.43821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338460PMC
January 2019

Triazole-bearing calixpyrroles: strong halide binding affinities through multiple N-H and C-H hydrogen bonds.

Chem Commun (Camb) 2018 Sep;54(77):10863-10865

Department of Chemistry, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea.

Triazole-bearing calixpyrroles (TCPs) were synthesized as artificial anion binding receptors. The additional C-HX hydrogen bonding interaction induced strong binding affinity towards halide ions. Using this strong binding affinity, Cl- was successfully extracted from the aqueous to organic phase.
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http://dx.doi.org/10.1039/c8cc06385kDOI Listing
September 2018

Integrating the Epigenome to Identify Drivers of Hepatocellular Carcinoma.

Hepatology 2019 02 5;69(2):639-652. Epub 2019 Jan 5.

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN.

Disruption of epigenetic mechanisms has been intimately linked to the etiology of human cancer. Understanding how these epigenetic mechanisms (including DNA methylation [5mC], hydroxymethylation [5hmC], and histone post-translational modifications) work in concert to drive cancer initiation and progression remains unknown. Hepatocellular carcinoma (HCC) is increasing in frequency in Western countries but lacks efficacious treatments. The epigenome of HCC remains understudied. To better understand the epigenetic underpinnings of HCC, we performed a genome-wide assessment of 5mC, 5hmC, four histone modifications linked to promoter/enhancer function (H3K4me1, H3K27ac, H3K4me3, and H3K27me3), and transcription across normal, cirrhotic, and HCC liver tissue. Implementation of bioinformatic strategies integrated these epigenetic marks with each other and with transcription to provide a comprehensive epigenetic profile of how and when the liver epigenome is perturbed during progression to HCC. Our data demonstrate significant deregulation of epigenetic regulators combined with disruptions in the epigenome hallmarked by profound loss of 5hmC, locus-specific gains in 5mC and 5hmC, and markedly altered histone modification profiles, particularly remodeling of enhancers. Data integration demonstrates that these marks collaborate to influence transcription (e.g., hyper-5hmC in HCC-gained active enhancers is linked to elevated expression) of genes regulating HCC proliferation. Two such putative epigenetic driver loci identified through our integrative approach, COMT and FMO3, increase apoptosis and decrease cell viability in liver-derived cancer cell lines when ectopically re-expressed. Conclusion: Altogether, integration of multiple epigenetic parameters is a powerful tool for identifying epigenetically regulated drivers of HCC and elucidating how epigenome deregulation contributes to liver disease and HCC.
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http://dx.doi.org/10.1002/hep.30211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351162PMC
February 2019

ZBTB24 is a transcriptional regulator that coordinates with DNMT3B to control DNA methylation.

Nucleic Acids Res 2018 11;46(19):10034-10051

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Stabile 12-58, Rochester, MN 55905, USA.

The interplay between transcription factors and epigenetic writers like the DNA methyltransferases (DNMTs), and the role of this interplay in gene expression, is being increasingly appreciated. ZBTB24, a poorly characterized zinc-finger protein, or the de novo methyltransferase DNMT3B, when mutated, cause Immunodeficiency, Centromere Instability, and Facial anomalies (ICF) syndrome, suggesting an underlying mechanistic link. Chromatin immunoprecipitation coupled with loss-of-function approaches in model systems revealed common loci bound by ZBTB24 and DNMT3B, where they function to regulate gene body methylation. Genes coordinately regulated by ZBTB24 and DNMT3B are enriched for molecular mechanisms essential for cellular homeostasis, highlighting the importance of the ZBTB24-DNMT3B interplay in maintaining epigenetic patterns required for normal cellular function. We identify a ZBTB24 DNA binding motif, which is contained within the promoters of most of its transcriptional targets, including CDCA7, AXIN2, and OSTC. Direct binding of ZBTB24 at the promoters of these genes targets them for transcriptional activation. ZBTB24 binding at the promoters of RNF169 and CAMKMT, however, targets them for transcriptional repression. The involvement of ZBTB24 targets in diverse cellular programs, including the VDR/RXR and interferon regulatory pathways, suggest that ZBTB24's role as a transcriptional regulator is not restricted to immune cells.
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http://dx.doi.org/10.1093/nar/gky682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212772PMC
November 2018

A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma.

Nat Commun 2018 07 27;9(1):2949. Epub 2018 Jul 27.

Institute for Cancer Genetics, Department of Pediatrics and Department of Genetics and Development, Irving Cancer Research Center, Columbia University, 1130 St. Nicholas Avenue, New York, NY, 10032, USA.

Temozolomide (TMZ) was used for the treatment of glioblastoma (GBM) for over a decade, but its treatment benefits are limited by acquired resistance, a process that remains incompletely understood. Here we report that an enhancer, located between the promoters of marker of proliferation Ki67 (MKI67) and O6-methylguanine-DNA-methyltransferase (MGMT) genes, is activated in TMZ-resistant patient-derived xenograft (PDX) lines and recurrent tumor samples. Activation of the enhancer correlates with increased MGMT expression, a major known mechanism for TMZ resistance. We show that forced activation of the enhancer in cell lines with low MGMT expression results in elevated MGMT expression. Deletion of this enhancer in cell lines with high MGMT expression leads to a dramatic reduction of MGMT and a lesser extent of Ki67 expression, increased TMZ sensitivity, and impaired proliferation. Together, these studies uncover a mechanism that regulates MGMT expression, confers TMZ resistance, and potentially regulates tumor proliferation.
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http://dx.doi.org/10.1038/s41467-018-05373-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063898PMC
July 2018

A droplet microfluidic platform for efficient enzymatic chromatin digestion enables robust determination of nucleosome positioning.

Lab Chip 2018 08;18(17):2583-2592

Department of Chemistry, University of Michigan, Ann Arbor, MI, USA.

The first step in chromatin-based epigenetic assays involves the fragmentation of chromatin to facilitate precise genomic localization of the associated DNA. Here, we report the development of a droplet microfluidic device that can rapidly and efficiently digest chromatin into single nucleosomes starting from whole-cell input material offering simplified and automated processing compared to conventional manual preparation. We demonstrate the digestion of chromatin from 2500-125 000 Jurkat cells using micrococcal nuclease for enzymatic processing. We show that the yield of mononucleosomal DNA can be optimized by controlling enzyme concentration and incubation time, with resulting mononucleosome yields exceeding 80%. Bioinformatic analysis of sequenced mononucleosomal DNA (MNase-seq) indicated a high degree of reproducibility and concordance (97-99%) compared with conventionally processed preparations. Our results demonstrate the feasibility of robust and automated nucleosome preparation using a droplet microfluidic platform for nucleosome positioning and downstream epigenomic assays.
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http://dx.doi.org/10.1039/c8lc00599kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103843PMC
August 2018

Uhrf1 regulates active transcriptional marks at bivalent domains in pluripotent stem cells through Setd1a.

Nat Commun 2018 07 3;9(1):2583. Epub 2018 Jul 3.

Department of Genetics, Yale Stem Cell Center, Yale Child Study Center, Yale School of Medicine, New Haven, CT, 06520, USA.

Embryonic stem cells (ESCs) maintain pluripotency through unique epigenetic states. When ESCs commit to a specific lineage, epigenetic changes in histones and DNA accompany the transition to specialized cell types. Investigating how epigenetic regulation controls lineage specification is critical in order to generate the required cell types for clinical applications. Uhrf1 is a widely known hemi-methylated DNA-binding protein, playing a role in DNA methylation through the recruitment of Dnmt1 and in heterochromatin formation alongside G9a, Trim28, and HDACs. Although Uhrf1 is not essential in ESC self-renewal, it remains elusive how Uhrf1 regulates cell specification. Here we report that Uhrf1 forms a complex with the active trithorax group, the Setd1a/COMPASS complex, to maintain bivalent histone marks, particularly those associated with neuroectoderm and mesoderm specification. Overall, our data demonstrate that Uhrf1 safeguards proper differentiation via bivalent histone modifications.
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http://dx.doi.org/10.1038/s41467-018-04818-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030064PMC
July 2018

Multivalent Mannose-Decorated NIR Nanoprobes for Targeting Pan Lymph Nodes.

Chem Eng J 2018 May 3;340:51-57. Epub 2018 Jan 3.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Lymphadenectomy is a prerequisite for most malignancies to define the precise staging of cancer, as well as resect the possible metastases completely. While it improves prognosis, lymphadenectomy often causes postoperative edema or bleeding because of unclear surgical margins. In this study, we synthesized near-infrared (NIR) fluorescent nanoprobes with conjugating various mannose moieties on the surface to target macrophages in the lymph node. Armed with these NIR nanoprobes, we demonstrated the feasibility of intraoperative pan lymph nodes (PLN) mapping and real-time optical imaging under the NIR fluorescence imaging system. We found that even single mannose-conjugated ZW800-1 showed specific uptake in lymph nodes within 4 h, and multiple mannose-employed polyrotaxanes highlighted PLN efficiently with low background signals in major organs. This technology can help surgeons perform lymphadenectomy with ease and safety by identifying all regional lymph nodes proficiently after a single intravenous injection of NIR nanoprobes.
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http://dx.doi.org/10.1016/j.cej.2018.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022841PMC
May 2018

H3.3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers.

Elife 2018 06 22;7. Epub 2018 Jun 22.

Department of Pediatrics and Department of Genetics and Development, Institute for Cancer Genetics, Irving Cancer Research Center, Columbia University, New York, United States.

Expression of histone H3.3K27M mutant proteins in human diffuse intrinsic pontine glioma (DIPG) results in a global reduction of tri-methylation of H3K27 (H3K27me3), and paradoxically, H3K27me3 peaks remain at hundreds of genomic loci, a dichotomous change that lacks mechanistic insights. Here, we show that the PRC2 complex is sequestered at poised enhancers, but not at active promoters with high levels of H3.3K27M proteins, thereby contributing to the global reduction of H3K27me3. Moreover, the levels of H3.3K27M proteins are low at the retained H3K27me3 peaks and consequently having minimal effects on the PRC2 activity at these loci. H3K27me3-mediated silencing at specific tumor suppressor genes, including Wilms Tumor 1, promotes proliferation of DIPG cells. These results support a model in which the PRC2 complex is redistributed to poised enhancers in H3.3K27M mutant cells and contributes to tumorigenesis in part by locally enhancing H3K27me3, and hence silencing of tumor suppressor genes.
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http://dx.doi.org/10.7554/eLife.36696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033537PMC
June 2018

Distinct epigenetic landscapes underlie the pathobiology of pancreatic cancer subtypes.

Nat Commun 2018 05 17;9(1):1978. Epub 2018 May 17.

Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, 14 rue Corvisart, Paris, 75013, France.

Recent studies have offered ample insight into genome-wide expression patterns to define pancreatic ductal adenocarcinoma (PDAC) subtypes, although there remains a lack of knowledge regarding the underlying epigenomics of PDAC. Here we perform multi-parametric integrative analyses of chromatin immunoprecipitation-sequencing (ChIP-seq) on multiple histone modifications, RNA-sequencing (RNA-seq), and DNA methylation to define epigenomic landscapes for PDAC subtypes, which can predict their relative aggressiveness and survival. Moreover, we describe the state of promoters, enhancers, super-enhancers, euchromatic, and heterochromatic regions for each subtype. Further analyses indicate that the distinct epigenomic landscapes are regulated by different membrane-to-nucleus pathways. Inactivation of a basal-specific super-enhancer associated pathway reveals the existence of plasticity between subtypes. Thus, our study provides new insight into the epigenetic landscapes associated with the heterogeneity of PDAC, thereby increasing our mechanistic understanding of this disease, as well as offering potential new markers and therapeutic targets.
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http://dx.doi.org/10.1038/s41467-018-04383-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958058PMC
May 2018

Distinctive epigenomes characterize glioma stem cells and their response to differentiation cues.

Genome Biol 2018 03 27;19(1):43. Epub 2018 Mar 27.

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.

Background: Glioma stem cells (GSCs) are a subpopulation of stem-like cells that contribute to glioblastoma (GBM) aggressiveness, recurrence, and resistance to radiation and chemotherapy. Therapeutically targeting the GSC population may improve patient survival, but unique vulnerabilities need to be identified.

Results: We isolate GSCs from well-characterized GBM patient-derived xenografts (PDX), characterize their stemness properties using immunofluorescence staining, profile their epigenome including 5mC, 5hmC, 5fC/5caC, and two enhancer marks, and define their transcriptome. Fetal brain-derived neural stem/progenitor cells are used as a comparison to define potential unique and common molecular features between these different brain-derived cells with stem properties. Our integrative study reveals that abnormal expression of ten-eleven-translocation (TET) family members correlates with global levels of 5mC and 5fC/5caC and may be responsible for the distinct levels of these marks between glioma and neural stem cells. Heterogenous transcriptome and epigenome signatures among GSCs converge on several genes and pathways, including DNA damage response and cell proliferation, which are highly correlated with TET expression. Distinct enhancer landscapes are also strongly associated with differential gene regulation between glioma and neural stem cells; they exhibit unique co-localization patterns with DNA epigenetic mark switching events. Upon differentiation, glioma and neural stem cells exhibit distinct responses with regard to TET expression and DNA mark changes in the genome and GSCs fail to properly remodel their epigenome.

Conclusions: Our integrative epigenomic and transcriptomic characterization reveals fundamentally distinct yet potentially targetable biologic features of GSCs that result from their distinct epigenomic landscapes.
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http://dx.doi.org/10.1186/s13059-018-1420-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872397PMC
March 2018