DOCSLIB.ORG

Enhancer Priming by H3K4 Methyltransferase MLL4 Controls Cell Fate Transition

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Enhancer Priming by H3K4 Methyltransferase MLL4 Controls Cell Fate Transition Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition Chaochen Wanga, Ji-Eun Leea, Binbin Laia, Todd S. Macfarlanb, Shiliyang Xua, Lenan Zhuanga, Chengyu Liuc, Weiqun Pengd,e, and Kai Gea,1 aLaboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; bDivision of Developmental Biology, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; cTransgenic Core, Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; dDepartment of Physics, The George Washington University, Washington, DC 20052; and eDepartment of Anatomy and Regenerative Biology, The George Washington University, Washington, DC 20052 Edited by Eric N. Olson, University of Texas Southwestern Medical Center, Dallas, TX, and approved August 26, 2016 (received for review April 29, 2016) Transcriptional enhancers control cell-type–specific gene expres- excellent models for studying cell fate transition and the underlying sion. Primed enhancers are marked by histone H3 lysine 4 (H3K4) molecular mechanism. mono/di-methylation (H3K4me1/2). Active enhancers are further MLL4 is a major enhancer H3K4 mono- and di-methyltransfer- marked by H3K27 acetylation (H3K27ac). Mixed-lineage leukemia ase with partial functional redundancy with MLL3 in mammalian 4 (MLL4/KMT2D) is a major enhancer H3K4me1/2 methyltransferase cells (7, 8). MLL4 colocalizes with lineage-determining TFs on AEs with functional redundancy with MLL3 (KMT2C). However, its role in during adipogenesis and myogenesis. Furthermore, MLL4 is re- cell fate maintenance and transition is poorly understood. Here, we quired for enhancer activation, cell-type–specific gene expression, show in mouse embryonic stem cells (ESCs) that MLL4 associates and cell differentiation during adipogenesis and myogenesis (8). with, but is surprisingly dispensable for the maintenance of, active These observations prompted us to investigate whether MLL4 enhancers of cell-identity genes. As a result, MLL4 is dispensable for plays a more general role in the control of cell fate transition and cell-identity gene expression and self-renewal in ESCs. In contrast, how MLL4 regulates enhancer activation. In this study, we use mainly MLL4 is required for enhancer-binding of H3K27 acetyltransferase ESC differentiation and somatic cell reprogramming as model sys- p300, enhancer activation, and induction of cell-identity genes during tems to explore functions and mechanisms of MLL4 in enhancer CELL BIOLOGY ESC differentiation. MLL4 protein, rather than MLL4-mediated H3K4 activation, cell-identity maintenance, and cell fate transition. methylation, controls p300 recruitment to enhancers. We also show that, in somatic cells, MLL4 is dispensable for maintaining cell iden- Results tity but essential for reprogramming into induced pluripotent stem MLL4 Associates with Active Enhancers on Cell-Identity Genes in ESCs. cells. These results indicate that, although enhancer priming by MLL4 is essential for early embryonic development in mice MLL4 is dispensable for cell-identity maintenance, it controls cell fate whereas MLL3 is dispensable. In cultured cells, MLL3 partially transition by orchestrating p300-mediated enhancer activation. compensates for the loss of MLL4 (8). To investigate the role of MLL4 in ESC self-renewal and differentiation, we derived Mll3 − − enhancer | MLL4/KMT2D | H3K4 methyltransferase | cell fate transition | KO and Mll4 conditional KO (Mll3 / Mll4f/f, hereafter referred p300 to as f/f) ESCs from blastocysts. By transfecting these cells with a Cre-expressing plasmid to delete the Mll4 gene, we generated n mammalian cells, enhancers coordinate with promoters to Iprecisely control cell-type–specific gene transcription, which Significance determines the cell identity (1, 2). Comprehensive genome-wide studies have provided insights into the chromatin signatures of Transcriptional enhancers control cell-identity gene expression enhancers. Primed enhancers are marked by H3K4me1/2. Active and thus determine cell identity. Enhancers are primed by enhancers (AEs) are further marked by the histone acetyl- histone H3K4 mono-/di-methyltransferase MLL4 before they transferases CBP/p300-mediated H3K27ac (3). Recent studies are activated by histone H3K27 acetyltransferase p300. Here, classify AEs into typical enhancers and superenhancers. Super- we show that MLL4 is dispensable for cell-identity mainte- enhancers are clusters of AEs bound by lineage-determining nance but essential for cell fate transition using several model transcription factors (TFs). Compared with typical enhancers, – systems including embryonic stem cell (ESC) differentiation superenhancers are more cell-lineage specific and control cell toward somatic cells and somatic cell reprogramming into ESC- identity (4). Enhancer activation is orchestrated through a regu- like cells. Mechanistically, MLL4 is dispensable for maintaining latory network involving lineage-determining TFs and chromatin- p300 binding on active enhancers of cell-identity genes but is modifying complexes (2). However, how chromatin-modifying required for p300 binding on enhancers activated during cell complexes regulate enhancer activation and cell fate transition is fate transition. These results indicate that, although enhancer poorly understood. priming by MLL4 is dispensable for cell-identity maintenance, it Embryonic stem cells (ESCs) derived from blastocysts are ca- controls cell fate transition by orchestrating p300-mediated pable of unlimited replication in vitro, a property known as ESC enhancer activation. self-renewal. ESC identity is maintained during self-renewal. ESC self-renewal is controlled by a core circuitry of TFs including Oct4, Author contributions: C.W. and K.G. designed research; C.W., J.-E.L., L.Z., and K.G. per- Sox2, and Nanog (4). ESCs can rapidly respond to environmental formed research; C.W., T.S.M., and C.L. contributed new reagents/analytic tools; C.W., J.-E.L., cues and differentiate into three germ layers—ectoderm, endo- B.L., S.X., W.P., and K.G. analyzed data; and C.W., W.P., and K.G. wrote the paper. derm, and mesoderm—which consist of all cell lineages within The authors declare no conflict of interest. days (5). Differentiated somatic cells can also be converted back to This article is a PNAS Direct Submission. the pluripotent stage by ectopic expression of Oct4 and Sox2 Data deposition: The sequence reported in this paper has been deposited in the Gene together with Klf4 and c-Myc, a process known as somatic cell Expression Omnibus database (accession no. GSE50534). reprogramming into induced pluripotent stem cells (iPSCs) (6). The 1To whom correspondence should be addressed. Email: [email protected]. dramatic changes of cell identity that accompany ESC differentia- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. tion and somatic cell reprogramming make these two processes 1073/pnas.1606857113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1606857113 PNAS Early Edition | 1of6 Downloaded by guest on October 1, 2021 + Mll3/Mll4 double KO (DKO) ESCs. Deletion of Mll4 from the f/f Motif analysis showed that MLL4 AEs were enriched with ESCs resulted in an approximately twofold decrease of global motifs of major ESC TFs including Sox2, Oct4, Smad2/3, Nanog, H3K4me1 and ∼30% decreases of global H3K4me2 and H3K27ac and Klf4 (Fig. 1D). By comparing the genomic localization of with little effect on H3K4me3 and H3K9ac levels (Fig. 1A and SI MLL4 with those of Oct4, Sox2, and Nanog (O/S/N) and the Appendix, Fig. S1A). Thus, MLL3 and MLL4 are H3K4me1/2 H3K27 acetyltransferase p300 that marks AEs (4, 9), we found methyltransferases in ESCs. that MLL4 colocalized with O/S/N and p300 on AEs (Fig. 1E). A Next we performed ChIP-Seq (chromatin immunoprecipitation physical interaction between MLL4 and Oct4 was also observed in coupled with DNA sequencing) of MLL4 in both f/f and DKO ESCs (SI Appendix,Fig.S1B), consistent with the previous report ESCs. After filtering out nonspecific signals observed in the DKO that the MLL4 complex physically interacts with pluripotency cells (8), 12,383 high-confidence MLL4 binding sites were identi- TFs (10). Thus, MLL4 colocalizes with pluripotency TFs on AEs fied in f/f ESCs, the vast majority of which were marked by in ESCs. H3K4me1 and/or H3K4me2 (Fig. 1B). Consistent with our pre- Superenhancers (SEs), densely occupied by master TFs, are lineage-specific and associate with highly expressed cell-identity vious findings in adipocytes and myocytes (8), ChIP-Seq revealed genes (4, 11). We found that ∼90% of ESC SEs were occupied by that MLL4 was preferentially enriched on AEs in ESCs (Fig. 1C). MLL4. In contrast, only ∼30% of typical enhancers (TEs) were + MLL4 (SI Appendix, Fig. S1C). SEs had higher levels of MLL4- binding density comparing to TEs in ESCs (SI Appendix, Fig. + S1D). Moreover, genes associated with MLL4 SEs were expressed at significantly higher levels than those with TEs (SI Appendix, Fig. S1E). Consistently, gene ontology (GO) analysis of genes + associated with the 5,918 MLL4 AEs identified stem cell development, maintenance, and differentiation as the top func- tional categories (SI Appendix, Fig. S1F). For example, MLL4 colocalized with Oct4 and p300 on AEs of the ESC identity genes Nanog, Oct4 (Pou5f1), and
Load more

Recommended publications
  • Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin
    cells Review Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin Agnieszka Bochy ´nska,Juliane Lüscher-Firzlaff and Bernhard Lüscher * ID Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Pauwelsstrasse 30, 52057 Aachen, Germany; [email protected] (A.B.); jluescher-fi[email protected] (J.L.-F.) * Correspondence: [email protected]; Tel.: +49-241-8088850; Fax: +49-241-8082427 Received: 18 January 2018; Accepted: 27 February 2018; Published: 2 March 2018 Abstract: Regulation of gene expression is achieved by sequence-specific transcriptional regulators, which convey the information that is contained in the sequence of DNA into RNA polymerase activity. This is achieved by the recruitment of transcriptional co-factors. One of the consequences of co-factor recruitment is the control of specific properties of nucleosomes, the basic units of chromatin, and their protein components, the core histones. The main principles are to regulate the position and the characteristics of nucleosomes. The latter includes modulating the composition of core histones and their variants that are integrated into nucleosomes, and the post-translational modification of these histones referred to as histone marks. One of these marks is the methylation of lysine 4 of the core histone H3 (H3K4). While mono-methylation of H3K4 (H3K4me1) is located preferentially at active enhancers, tri-methylation (H3K4me3) is a mark found at open and potentially active promoters. Thus, H3K4 methylation is typically associated with gene transcription. The class 2 lysine methyltransferases (KMTs) are the main enzymes that methylate H3K4. KMT2 enzymes function in complexes that contain a necessary core complex composed of WDR5, RBBP5, ASH2L, and DPY30, the so-called WRAD complex.
    [Show full text]
  • Utx Is Required for Proper Induction of Ectoderm and Mesoderm During Differentiation of Embryonic Stem Cells
    Utx Is Required for Proper Induction of Ectoderm and Mesoderm during Differentiation of Embryonic Stem Cells Cristina Morales Torres1,2, Anne Laugesen1,2, Kristian Helin1,2,3* 1 Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark, 2 Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark, 3 The Danish Stem Cell Center, University of Copenhagen, Copenhagen, Denmark Abstract Embryonic development requires chromatin remodeling for dynamic regulation of gene expression patterns to ensure silencing of pluripotent transcription factors and activation of developmental regulators. Demethylation of H3K27me3 by the histone demethylases Utx and Jmjd3 is important for the activation of lineage choice genes in response to developmental signals. To further understand the function of Utx in pluripotency and differentiation we generated Utx knockout embryonic stem cells (ESCs). Here we show that Utx is not required for the proliferation of ESCs, however, Utx contributes to the establishment of ectoderm and mesoderm in vitro. Interestingly, this contribution is independent of the catalytic activity of Utx. Furthermore, we provide data showing that the Utx homologue, Uty, which is devoid of detectable demethylase activity, and Jmjd3 partly compensate for the loss of Utx. Taken together our results show that Utx is required for proper formation of ectoderm and mesoderm in vitro, and that Utx, similar to its C.elegans homologue, has demethylase dependent and independent functions. Citation: Morales Torres C, Laugesen A, Helin K (2013) Utx Is Required for Proper Induction of Ectoderm and Mesoderm during Differentiation of Embryonic Stem Cells. PLoS ONE 8(4): e60020. doi:10.1371/journal.pone.0060020 Editor: Qiang Wu, National University of Singapore, Singapore Received December 13, 2012; Accepted February 21, 2013; Published April 3, 2013 Copyright: ß 2013 Morales Torres et al.
    [Show full text]
  • Potential Genotoxicity from Integration Sites in CLAD Dogs Treated Successfully with Gammaretroviral Vector-Mediated Gene Therapy
    Gene Therapy (2008) 15, 1067–1071 & 2008 Nature Publishing Group All rights reserved 0969-7128/08 $30.00 www.nature.com/gt SHORT COMMUNICATION Potential genotoxicity from integration sites in CLAD dogs treated successfully with gammaretroviral vector-mediated gene therapy M Hai1,3, RL Adler1,3, TR Bauer Jr1,3, LM Tuschong1, Y-C Gu1,XWu2 and DD Hickstein1 1Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA and 2Laboratory of Molecular Technology, Scientific Applications International Corporation-Frederick, National Cancer Institute-Frederick, Frederick, Maryland, USA Integration site analysis was performed on six dogs with in hematopoietic stem cells. Integrations clustered around canine leukocyte adhesion deficiency (CLAD) that survived common insertion sites more frequently than random. greater than 1 year after infusion of autologous CD34+ bone Despite potential genotoxicity from RIS, to date there has marrow cells transduced with a gammaretroviral vector been no progression to oligoclonal hematopoiesis and no expressing canine CD18. A total of 387 retroviral insertion evidence that vector integration sites influenced cell survival sites (RIS) were identified in the peripheral blood leukocytes or proliferation. Continued follow-up in disease-specific from the six dogs at 1 year postinfusion. A total of 129 RIS animal models such as CLAD will be required to provide an were identified in CD3+ T-lymphocytes and 102 RIS in accurate estimate
    [Show full text]
  • MLL3/MLL4 Methyltransferase Activities Regulate Embryonic Stem Cell
    bioRxiv preprint doi: https://doi.org/10.1101/2020.09.14.296558; this version posted September 14, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 MLL3/MLL4 methyltransferase activities regulate embryonic stem cell 2 differentiation independent of enhancer H3K4me1 3 4 Guojia Xie1, Ji-Eun Lee1, Kaitlin McKernan1, Young-Kwon Park1, Younghoon Jang1, Chengyu Liu2, Weiqun 5 Peng3 and Kai Ge1* 6 7 1Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney 8 Diseases, National Institutes of Health, Bethesda, MD 20892, USA 9 2Transgenic Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 10 20892, USA 11 3Departments of Physics and Anatomy and Cell Biology, The George Washington University, Washington, 12 DC 20052, USA 13 14 *To whom correspondence should be addressed. (Email: [email protected]) 15 16 17 18 19 Highlights 20 ● Simultaneous elimination of MLL3 and MLL4 enzymatic activities leads to early embryonic lethality in 21 mice 22 ● MLL3/4 enzymatic activities are dispensable for ESC differentiation towards the three germ layers 23 ● ESCs lacking MLL3/4 enzymatic activities show cavitation defects during EB differentiation, likely due 24 to impaired VE induction 25 ● MLL3/4-catalyzed H3K4me1 is dispensable for enhancer activation in ESC differentiation 26 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.14.296558; this version posted September 14, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder.
    [Show full text]
  • Functional Annotation of Human Long Noncoding Rnas Using Chromatin
    bioRxiv preprint doi: https://doi.org/10.1101/2021.01.13.426305; this version posted January 14, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Funconal annotaon of human long noncoding RNAs using chroman conformaon data Saumya Agrawal1, Tanvir Alam2, Masaru Koido1,3, Ivan V. Kulakovskiy4,5, Jessica Severin1, Imad ABugessaisa1, Andrey Buyan5,6, Josee Dos&e7, Masayoshi Itoh1,8, Naoto Kondo9, Yunjing Li10, Mickaël Mendez11, Jordan A. Ramilowski1,12, Ken Yagi1, Kayoko Yasuzawa1, CHi Wai Yip1, Yasushi Okazaki1, MicHael M. Ho9man11,13,14,15, Lisa Strug10, CHung CHau Hon1, CHikashi Terao1, Takeya Kasukawa1, Vsevolod J. Makeev4,16, Jay W. SHin1, Piero Carninci1, MicHiel JL de Hoon1 1RIKEN Center for Integra&ve Medical Sciences, YokoHama, Japan. 2College of Science and Engineering, Hamad Bin KHalifa University, DoHa, Qatar. 3Ins&tute of Medical Science, THe University of Tokyo, Tokyo, Japan. 4Vavilov Ins&tute of General Gene&cs, Russian Academy of Sciences, Moscow, Russia. 5Ins&tute of Protein ResearcH, Russian Academy of Sciences, PusHcHino, Russia. 6Faculty of Bioengineering and Bioinforma&cs, Lomonosov Moscow State University, Moscow, Russia. 7Department of BiocHemistry, Rosalind and Morris Goodman Cancer ResearcH Center, McGill University, Montréal, QuéBec, Canada. 8RIKEN Preven&ve Medicine and Diagnosis Innova&on Program, Wako, Japan. 9RIKEN Center for Life Science TecHnologies, YokoHama, Japan. 10Division of Biosta&s&cs, Dalla Lana ScHool of PuBlic HealtH, University of Toronto, Toronto, Ontario, Canada. 11Department of Computer Science, University of Toronto, Toronto, Ontario, Canada. 12Advanced Medical ResearcH Center, YokoHama City University, YokoHama, Japan.
    [Show full text]
  • A Small UTX Stabilization Domain of Trr Is Conserved Within Mammalian MLL3-4/COMPASS and Is Sufficient to Rescue Loss of Viability in Null Animals
    Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press A small UTX stabilization domain of Trr is conserved within mammalian MLL3-4/ COMPASS and is sufficient to rescue loss of viability in null animals Ryan Rickels,1 Lu Wang,1 Marta Iwanaszko,1 Patrick A. Ozark,1 Marc A. Morgan,1 Andrea Piunti,1 Natalia Khalatyan,2 Shimaa H.A. Soliman,1 Emily J. Rendleman,1 Jeffrey N. Savas,2 Edwin R. Smith,1 and Ali Shilatifard1 1Simpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics, 2Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA Catalytic-inactivating mutations within the Drosophila enhancer H3K4 mono-methyltransferase Trr and its mammalian homologs, MLL3/4, cause only minor changes in gene expression compared with whole-gene deletions for these COMPASS members. To identify essential histone methyltransferase-independent functions of Trr, we screened to identify a minimal Trr domain sufficient to rescue Trr-null lethality and demonstrate that this domain binds and stabilizes Utx in vivo. Using the homologous MLL3/MLL4 human sequences, we mapped a short ∼80- amino-acid UTX stabilization domain (USD) that promotes UTX stability in the absence of the rest of MLL3/4. Nuclear UTX stability is enhanced when the USD is fused with the MLL4 HMG-box. Thus, COMPASS-dependent UTX stabilization is an essential noncatalytic function of Trr/MLL3/MLL4, suggesting that stabilizing UTX could be a therapeutic strategy for cancers with MLL3/4 loss-of-function mutations. [Keywords: COMPASS; chromatin; epigenetics; transcription] Supplemental material is available for this article.
    [Show full text]
  • Enhancer Priming by H3K4 Methyltransferase MLL4 Controls Cell Fate Transition
    Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition Chaochen Wanga, Ji-Eun Leea, Binbin Laia, Todd S. Macfarlanb, Shiliyang Xua, Lenan Zhuanga, Chengyu Liuc, Weiqun Pengd,e, and Kai Gea,1 aLaboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; bDivision of Developmental Biology, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; cTransgenic Core, Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; dDepartment of Physics, The George Washington University, Washington, DC 20052; and eDepartment of Anatomy and Regenerative Biology, The George Washington University, Washington, DC 20052 Edited by Eric N. Olson, University of Texas Southwestern Medical Center, Dallas, TX, and approved August 26, 2016 (received for review April 29, 2016) Transcriptional enhancers control cell-type–specific gene expres- excellent models for studying cell fate transition and the underlying sion. Primed enhancers are marked by histone H3 lysine 4 (H3K4) molecular mechanism. mono/di-methylation (H3K4me1/2). Active enhancers are further MLL4 is a major enhancer H3K4 mono- and di-methyltransfer- marked by H3K27 acetylation (H3K27ac). Mixed-lineage leukemia ase with partial functional redundancy with MLL3 in mammalian 4 (MLL4/KMT2D) is a major enhancer H3K4me1/2 methyltransferase cells (7, 8). MLL4 colocalizes with lineage-determining TFs on AEs with functional redundancy with MLL3 (KMT2C). However, its role in during adipogenesis and myogenesis. Furthermore, MLL4 is re- cell fate maintenance and transition is poorly understood. Here, we quired for enhancer activation, cell-type–specific gene expression, show in mouse embryonic stem cells (ESCs) that MLL4 associates and cell differentiation during adipogenesis and myogenesis (8).
    [Show full text]
  • Transcriptional and Epigenetic Control of Brown and Beige Adipose Cell Fate and Function
    REVIEWS Transcriptional and epigenetic control of brown and beige adipose cell fate and function Takeshi Inagaki1,2, Juro Sakai1,2 and Shingo Kajimura3 Abstract | White adipocytes store excess energy in the form of triglycerides, whereas brown and beige adipocytes dissipate energy in the form of heat. This thermogenic function relies on the activation of brown and beige adipocyte-specific gene programmes that are coordinately regulated by adipose-selective chromatin architectures and by a set of unique transcriptional and epigenetic regulators. A number of transcriptional and epigenetic regulators are also required for promoting beige adipocyte biogenesis in response to various environmental stimuli. A better understanding of the molecular mechanisms governing the generation and function of brown and beige adipocytes is necessary to allow us to control adipose cell fate and stimulate thermogenesis. This may provide a therapeutic approach for the treatment of obesity and obesity-associated diseases, such as type 2 diabetes. Interscapular BAT Adipose tissue has a central role in whole-body energy subjects who had previously lacked detectable BAT Brown adipose tissue (BAT) is a homeostasis. White adipose tissue (WAT) is the major depots before cold exposure, presumably owing to the specialized organ that adipose organ in mammals. It represents 10% or more emergence of new thermogenic adipocytes. This, then, produces heat. BAT is localized of the body weight of healthy adult humans and is leads to an increase in non-shivering thermogenesis in the interscapular and 6–9 perirenal regions of rodents specialized for the storage of excess energy. Humans and/or an improvement in insulin sensitivity . These and infants.
    [Show full text]
  • Histone Methylation Regulation in Neurodegenerative Disorders
    International Journal of Molecular Sciences Review Histone Methylation Regulation in Neurodegenerative Disorders Balapal S. Basavarajappa 1,2,3,4,* and Shivakumar Subbanna 1 1 Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA; [email protected] 2 New York State Psychiatric Institute, New York, NY 10032, USA 3 Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA 4 New York University Langone Medical Center, Department of Psychiatry, New York, NY 10016, USA * Correspondence: [email protected]; Tel.: +1-845-398-3234; Fax: +1-845-398-5451 Abstract: Advances achieved with molecular biology and genomics technologies have permitted investigators to discover epigenetic mechanisms, such as DNA methylation and histone posttransla- tional modifications, which are critical for gene expression in almost all tissues and in brain health and disease. These advances have influenced much interest in understanding the dysregulation of epigenetic mechanisms in neurodegenerative disorders. Although these disorders diverge in their fundamental causes and pathophysiology, several involve the dysregulation of histone methylation- mediated gene expression. Interestingly, epigenetic remodeling via histone methylation in specific brain regions has been suggested to play a critical function in the neurobiology of psychiatric disor- ders, including that related to neurodegenerative diseases. Prominently, epigenetic dysregulation currently brings considerable interest as an essential player in neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic lateral sclerosis (ALS) and drugs of abuse, including alcohol abuse disorder, where it may facilitate connections between genetic and environmental risk factors or directly influence disease-specific Citation: Basavarajappa, B.S.; Subbanna, S.
    [Show full text]
  • Loss of the Transcription Factor MAFB Limits β-Cell
    UCSF UC San Francisco Previously Published Works Title Loss of the transcription factor MAFB limits β-cell derivation from human PSCs. Permalink https://escholarship.org/uc/item/0zb338n9 Journal Nature communications, 11(1) ISSN 2041-1723 Authors Russell, Ronan Carnese, Phichitpol P Hennings, Thomas G et al. Publication Date 2020-06-02 DOI 10.1038/s41467-020-16550-9 Peer reviewed eScholarship.org Powered by the California Digital Library University of California ARTICLE https://doi.org/10.1038/s41467-020-16550-9 OPEN Loss of the transcription factor MAFB limits β-cell derivation from human PSCs Ronan Russell1, Phichitpol P. Carnese1, Thomas G. Hennings1, Emily M. Walker 2, Holger A. Russ 1,3, ✉ Jennifer S. Liu1, Simone Giacometti1, Roland Stein2 & Matthias Hebrok 1 Next generation sequencing studies have highlighted discrepancies in β-cells which exist between mice and men. Numerous reports have identified MAF BZIP Transcription Factor B 1234567890():,; (MAFB) to be present in human β-cells postnatally, while its expression is restricted to embryonic and neo-natal β-cells in mice. Using CRISPR/Cas9-mediated gene editing, coupled with endocrine cell differentiation strategies, we dissect the contribution of MAFB to β-cell development and function specifically in humans. Here we report that MAFB knockout hPSCs have normal pancreatic differentiation capacity up to the progenitor stage, but favor soma- tostatin- and pancreatic polypeptide–positive cells at the expense of insulin- and glucagon- producing cells during endocrine cell development. Our results describe a requirement for MAFB late in the human pancreatic developmental program and identify it as a distinguishing transcription factor within islet cell subtype specification.
    [Show full text]
  • The Role of the MLL-HOXA9 Axis in Normal and Malignant
    The Role of the MLL-HOXA9 Axis in Normal and Malignant Hematopoiesis by Jingya Wang A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Molecular and Cellular Pathology) in the University of Michigan 2013 Doctoral Committee: Professor Jay L. Hess, Chair Assistant Professor Tomasz Cierpicki Professor Eric R. Fearon Assistant Professor Maria E. Figueroa Professor Tom K. Kerppola Associate Professor Xiaochun Yu © Jingya Wang 2013 To My parents and My husband ii Acknowledgement This dissertation would not have been possible without the tremendous support and guidance from my advisor, Dr. Jay L. Hess. Jay’s enthusiasm and dedication towards scientific research have always been a great source of inspiration. His scientific vision and openness to novel ideas greatly influenced my scientific career. I would also like to thank Jay for encouraging me to pursue my interest in statistics and the opportunity to apply my knowledge to biomedical research. I deeply appreciate Jay’s invaluable advice and generous support for the next stage of my career. My sincere appreciations also go to Drs. Andrew Muntean and Maria (“Ken”) Figueroa. Throughout my graduate study, Andy was actively involved in many aspects of my projects and my scientific career, including providing technical assistance and scientific thinking, and most importantly, sharing his insights of science and being a better scientist. I could not have been where I am without his generous help. Ken led me into the field of high throughput sequencing data analysis, and patiently discussed experimental design to algorithm in details. Her presence also contributes greatly to the completion of this thesis.
    [Show full text]
  • JMJD3 Regulates CD4 T Cell Trafficking by Targeting Actin Cytoskeleton
    JMJD3 regulates CD4+ T cell trafficking by targeting actin cytoskeleton regulatory gene Pdlim4 Chuntang Fu, … , Helen Y. Wang, Rong-Fu Wang J Clin Invest. 2019;129(11):4745-4757. https://doi.org/10.1172/JCI128293. Research Article Autoimmunity Cell biology Immunology Graphical abstract Find the latest version: https://jci.me/128293/pdf The Journal of Clinical Investigation RESEARCH ARTICLE JMJD3 regulates CD4+ T cell trafficking by targeting actin cytoskeleton regulatory gene Pdlim4 Chuntang Fu,1,2 Qingtian Li,2 Jia Zou,2 Changsheng Xing,2 Mei Luo,2,3 Bingnan Yin,2 Junjun Chu,2 Jiaming Yu,2 Xin Liu,1,2 Helen Y. Wang,2 and Rong-Fu Wang1,2 1Institute of Bioscience and Technology, Texas A&M University Health Science Center, Houston, Texas, USA. 2Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas, USA. 3Xiangya Hospital, Central South University, Changsha, China. Histone H3K27 demethylase JMJD3 plays a critical role in gene expression and T cell differentiation. However, the role and mechanisms of JMJD3 in T cell trafficking remain poorly understood. Here, we show that JMJD3 deficiency in CD4+ T cells resulted in an accumulation of T cells in the thymus and reduction of T cell number in the secondary lymphoid organs. We identified PDLIM4 as a significantly downregulated target gene in JMJD3-deficient CD4+ T cells by gene profiling and ChIP-Seq analyses. We further showed that PDLIM4 functioned as an adaptor protein to interact with sphingosine-1 phosphate receptor 1 (S1P1) and filamentous actin (F-actin), thus serving as a key regulator of T cell trafficking.
    [Show full text]