Publications by authors named "Danielle Yi"

9 Publications

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Aging-dependent regulatory cells emerge in subcutaneous fat to inhibit adipogenesis.

Dev Cell 2021 Apr 9. Epub 2021 Apr 9.

Department of Nutritional Sciences & Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Program, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address:

Adipose tissue mass and adiposity change throughout the lifespan. During aging, while visceral adipose tissue (VAT) tends to increase, peripheral subcutaneous adipose tissue (SAT) decreases significantly. Unlike VAT, which is linked to metabolic diseases, including type 2 diabetes, SAT has beneficial effects. However, the molecular details behind the aging-associated loss of SAT remain unclear. Here, by comparing scRNA-seq of total stromal vascular cells of SAT from young and aging mice, we identify an aging-dependent regulatory cell (ARC) population that emerges only in SAT of aged mice and humans. ARCs express adipose progenitor markers but lack adipogenic capacity; they secrete high levels of pro-inflammatory chemokines, including Ccl6, to inhibit proliferation and differentiation of neighboring adipose precursors. We also found Pu.1 to be a driving factor for ARC development. We identify an ARC population and its capacity to inhibit differentiation of neighboring adipose precursors, correlating with aging-associated loss of SAT.
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http://dx.doi.org/10.1016/j.devcel.2021.03.026DOI Listing
April 2021

Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes.

Elife 2020 10 27;9. Epub 2020 Oct 27.

Department of Nutritional Sciences & Toxicology, University of California, Berkeley, Berkeley, United States.

Brown adipose tissue is a metabolically beneficial organ capable of dissipating chemical energy into heat, thereby increasing energy expenditure. Here, we identify Dot1l, the only known H3K79 methyltransferase, as an interacting partner of Zc3h10 that transcriptionally activates the promoter and other BAT genes. Through a direct interaction, Dot1l is recruited by Zc3h10 to the promoter regions of thermogenic genes to function as a coactivator by methylating H3K79. We also show that Dot1l is induced during brown fat cell differentiation and by cold exposure and that Dot1l and its H3K79 methyltransferase activity is required for thermogenic gene program. Furthermore, we demonstrate that Dot1l ablation in mice using -Cre prevents activation of and other target genes to reduce thermogenic capacity and energy expenditure, promoting adiposity. Hence, Dot1l plays a critical role in the thermogenic program and may present as a future target for obesity therapeutics.
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http://dx.doi.org/10.7554/eLife.59990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661038PMC
October 2020

Epigenetic dynamics of the thermogenic gene program of adipocytes.

Biochem J 2020 03;477(6):1137-1148

Department of Nutritional Sciences and Toxicology and Endocrinology Program, University of California, Berkeley, CA 94720, U.S.A.

Brown adipose tissue (BAT) is a metabolically beneficial organ capable of burning fat by dissipating chemical energy into heat, thereby increasing energy expenditure. Moreover, subcutaneous white adipose tissue can undergo so-called browning/beiging. The recent recognition of the presence of brown or beige adipocytes in human adults has attracted much attention to elucidate the molecular mechanism underlying the thermogenic adipose program. Many key transcriptional regulators critical for the thermogenic gene program centering on activating the UCP1 promoter, have been discovered. Thermogenic gene expression in brown adipocytes rely on co-ordinated actions of a multitude of transcription factors, including EBF2, PPARγ, Zfp516 and Zc3h10. These transcription factors probably integrate into a cohesive network for BAT gene program. Moreover, these transcription factors recruit epigenetic factors, such as LSD1 and MLL3/4, for specific histone signatures to establish the favorable chromatin landscape. In this review, we discuss advances made in understanding the molecular mechanism underlying the thermogenic gene program, particularly epigenetic regulation.
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http://dx.doi.org/10.1042/BCJ20190599DOI Listing
March 2020

Aifm2, a NADH Oxidase, Supports Robust Glycolysis and Is Required for Cold- and Diet-Induced Thermogenesis.

Mol Cell 2020 02 14;77(3):600-617.e4. Epub 2020 Jan 14.

Endocrinology Program, University of California, Berkeley, Berkeley, CA, USA; Department of Nutritional Sciences & Toxicology, University of California, Berkeley, Berkeley, CA, USA. Electronic address:

Brown adipose tissue (BAT) is highly metabolically active tissue that dissipates energy via UCP1 as heat, and BAT mass is correlated negatively with obesity. The presence of BAT/BAT-like tissue in humans renders BAT as an attractive target against obesity and insulin resistance. Here, we identify Aifm2, a NADH oxidoreductase domain containing flavoprotein, as a lipid droplet (LD)-associated protein highly enriched in BAT. Aifm2 is induced by cold as well as by diet. Upon cold or β-adrenergic stimulation, Aifm2 associates with the outer side of the mitochondrial inner membrane. As a unique BAT-specific first mammalian NDE (external NADH dehydrogenase)-like enzyme, Aifm2 oxidizes NADH to maintain high cytosolic NAD levels in supporting robust glycolysis and to transfer electrons to the electron transport chain (ETC) for fueling thermogenesis. Aifm2 in BAT and subcutaneous white adipose tissue (WAT) promotes oxygen consumption, uncoupled respiration, and heat production during cold- and diet-induced thermogenesis. Aifm2, thus, can ameliorate diet-induced obesity and insulin resistance.
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http://dx.doi.org/10.1016/j.molcel.2019.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031813PMC
February 2020

Zc3h10 Acts as a Transcription Factor and Is Phosphorylated to Activate the Thermogenic Program.

Cell Rep 2019 11;29(9):2621-2633.e4

Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Program, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address:

Brown adipose tissue harbors UCP1 to dissipate chemical energy as heat. However, the transcriptional network that governs the thermogenic gene program is incompletely understood. Zc3h10, a CCCH-type zinc finger protein, has recently been reported to bind RNA. However, we report here that Zc3h10 functions as a transcription factor to activate UCP1 not through the enhancer region, but by binding to a far upstream region of the UCP1 promoter. Upon sympathetic stimulation, Zc3h10 is phosphorylated at S126 by p38 mitogen-activated protein kinase (MAPK) to increase binding to the distal region of the UCP1 promoter. Zc3h10, as well as mutant Zc3h10, which cannot bind RNA, enhances thermogenic capacity and energy expenditure, protecting mice from diet-induced obesity. Conversely, Zc3h10 ablation in UCP1 cells in mice impairs thermogenic capacity and lowers oxygen consumption, leading to weight gain. Hence, Zc3h10 plays a critical role in the thermogenic gene program and may present future targets for obesity therapeutics.
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http://dx.doi.org/10.1016/j.celrep.2019.10.099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911170PMC
November 2019

Single-cell analyses demonstrate that a heme-GATA1 feedback loop regulates red cell differentiation.

Blood 2019 01 10;133(5):457-469. Epub 2018 Dec 10.

Department of Medicine, Division of Hematology, University of Washington, Seattle, WA; and.

Erythropoiesis is the complex, dynamic, and tightly regulated process that generates all mature red blood cells. To understand this process, we mapped the developmental trajectories of progenitors from wild-type, erythropoietin-treated, and -deleted mice at single-cell resolution. Importantly, we linked the quantity of each cell's surface proteins to its total transcriptome, which is a novel method. Deletion of results in high levels of intracellular heme, allowing us to identify heme-regulated circuitry. Our studies demonstrate that in early erythroid cells (CD71Ter119), heme increases ribosomal protein transcripts, suggesting that heme, in addition to upregulating globin transcription and translation, guarantees ample ribosomes for globin synthesis. In later erythroid cells (CD71Ter119), heme decreases GATA1, GATA1-target gene, and mitotic spindle gene expression. These changes occur quickly. For example, in confirmatory studies using human marrow erythroid cells, ribosomal protein transcripts and proteins increase, and GATA1 transcript and protein decrease, within 15 to 30 minutes of amplifying endogenous heme synthesis with aminolevulinic acid. Because GATA1 initiates heme synthesis, GATA1 and heme together direct red cell maturation, and heme stops GATA1 synthesis, our observations reveal a GATA1-heme autoregulatory loop and implicate GATA1 and heme as the comaster regulators of the normal erythroid differentiation program. In addition, as excessive heme could amplify ribosomal protein imbalance, prematurely lower GATA1, and impede mitosis, these data may help explain the ineffective (early termination of) erythropoiesis in Diamond Blackfan anemia and del(5q) myelodysplasia, disorders with excessive heme in colony-forming unit-erythroid/proerythroblasts, explain why these anemias are macrocytic, and show why children with GATA1 mutations have DBA-like clinical phenotypes.
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http://dx.doi.org/10.1182/blood-2018-05-850412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356983PMC
January 2019

RNASEQR--a streamlined and accurate RNA-seq sequence analysis program.

Nucleic Acids Res 2012 Mar 22;40(6):e42. Epub 2011 Dec 22.

Institute for Systems Biology, Seattle, WA 98109, USA.

Next-generation sequencing (NGS) technologies-based transcriptomic profiling method often called RNA-seq has been widely used to study global gene expression, alternative exon usage, new exon discovery, novel transcriptional isoforms and genomic sequence variations. However, this technique also poses many biological and informatics challenges to extracting meaningful biological information. The RNA-seq data analysis is built on the foundation of high quality initial genome localization and alignment information for RNA-seq sequences. Toward this goal, we have developed RNASEQR to accurately and effectively map millions of RNA-seq sequences. We have systematically compared RNASEQR with four of the most widely used tools using a simulated data set created from the Consensus CDS project and two experimental RNA-seq data sets generated from a human glioblastoma patient. Our results showed that RNASEQR yields more accurate estimates for gene expression, complete gene structures and new transcript isoforms, as well as more accurate detection of single nucleotide variants (SNVs). RNASEQR analyzes raw data from RNA-seq experiments effectively and outputs results in a manner that is compatible with a wide variety of specialized downstream analyses on desktop computers.
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http://dx.doi.org/10.1093/nar/gkr1248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315322PMC
March 2012

A CD133-related gene expression signature identifies an aggressive glioblastoma subtype with excessive mutations.

Proc Natl Acad Sci U S A 2011 Jan 10;108(4):1591-6. Epub 2011 Jan 10.

Institute for Systems Biology, Seattle, WA 98103, USA.

Cancer cells are heterogeneous and, it has been proposed, fall into at least two classes: the tumor-initiating cancer stem cells (CSC) and the more differentiated tumor cells. The transmembrane protein CD133 has been widely used to isolate putative CSC populations in several cancer types, but its validity as a CSC marker and hence its clinical ramifications remain controversial. Here, we conducted transcriptomic profiling of sorted CD133(+) and CD133(-) cells from human glioblastoma multiforme (GBM) and, by subtractive analysis, established a CD133 gene expression signature composed of 214 differentially expressed genes. Extensive computational comparisons with a compendium of published gene expression profiles reveal that the CD133 gene signature transcriptionally resembles human ES cells and in vitro cultured GBM stem cells, and this signature successfully distinguishes GBM from lower-grade gliomas. More importantly, the CD133 gene signature identifies an aggressive subtype of GBM seen in younger patients with shorter survival who bear excessive genomic mutations as surveyed through the Cancer Genome Atlas Network GBM mutation spectrum. Furthermore, the CD133 gene signature distinguishes higher-grade breast and bladder cancers from their lower-grade counterparts. Our systematic analysis provides molecular and genetic support for the stem cell-like nature of CD133(+) cells and an objective means for evaluating cancer aggressiveness.
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http://dx.doi.org/10.1073/pnas.1018696108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3029739PMC
January 2011

Integrated expression profiling and ChIP-seq analyses of the growth inhibition response program of the androgen receptor.

PLoS One 2009 Aug 11;4(8):e6589. Epub 2009 Aug 11.

Department of Urology, University of Washington, Seattle, WA, USA.

Background: The androgen receptor (AR) plays important roles in the development of male phenotype and in different human diseases including prostate cancers. The AR can act either as a promoter or a tumor suppressor depending on cell types. The AR proliferative response program has been well studied, but its prohibitive response program has not yet been thoroughly studied.

Methodology/principal Findings: Previous studies found that PC3 cells expressing the wild-type AR inhibit growth and suppress invasion. We applied expression profiling to identify the response program of PC3 cells expressing the AR (PC3-AR) under different growth conditions (i.e. with or without androgens and at different concentration of androgens) and then applied the newly developed ChIP-seq technology to identify the AR binding regions in the PC3 cancer genome. A surprising finding was that the comparison of MOCK-transfected PC3 cells with AR-transfected cells identified 3,452 differentially expressed genes (two fold cutoff) even without the addition of androgens (i.e. in ethanol control), suggesting that a ligand independent activation or extremely low-level androgen activation of the AR. ChIP-Seq analysis revealed 6,629 AR binding regions in the cancer genome of PC3 cells with an FDR (false discovery rate) cut off of 0.05. About 22.4% (638 of 2,849) can be mapped to within 2 kb of the transcription start site (TSS). Three novel AR binding motifs were identified in the AR binding regions of PC3-AR cells, and two of them share a core consensus sequence CGAGCTCTTC, which together mapped to 27.3% of AR binding regions (1,808/6,629). In contrast, only about 2.9% (190/6,629) of AR binding sites contains the canonical AR matrix M00481, M00447 and M00962 (from the Transfac database), which is derived mostly from AR proliferative responsive genes in androgen dependent cells. In addition, we identified four top ranking co-occupancy transcription factors in the AR binding regions, which include TEF1 (Transcriptional enhancer factor), GATA (GATA transcription factors), OCT (octamer transcription factors) and PU1 (PU.1 transcription factor).

Conclusions/significance: Our data provide a valuable data set in understanding the molecular basis for growth inhibition response program of the AR in prostate cancer cells, which can be exploited for developing novel prostate cancer therapeutic strategies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0006589PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720376PMC
August 2009