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  • 1
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    Role of Jhdm2a in regulating metabolic gene expression and obesity resistance (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-02-06
    Description: Recent studies indicate that the methylation state of histones can be dynamically regulated by histone methyltransferases and demethylases. The H3K9-specific demethylase Jhdm2a (also known as Jmjd1a and Kdm3a) has an important role in nuclear hormone receptor-mediated gene activation and male germ cell development. Through disruption of the Jhdm2a gene in mice, here we demonstrate that Jhdm2a is critically important in regulating the expression of metabolic genes. The loss of Jhdm2a function results in obesity and hyperlipidemia in mice. We provide evidence that the loss of Jhdm2a function disrupts beta-adrenergic-stimulated glycerol release and oxygen consumption in brown fat, and decreases fat oxidation and glycerol release in skeletal muscles. We show that Jhdm2a expression is induced by beta-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor alpha (Ppara) and Ucp1 expression. Furthermore, we demonstrate that beta-adrenergic activation-induced binding of Jhdm2a to the PPAR responsive element (PPRE) of the Ucp1 gene not only decreases levels of H3K9me2 (dimethylation of lysine 9 of histone H3) at the PPRE, but also facilitates the recruitment of Ppargamma and Rxralpha and their co-activators Pgc1alpha (also known as Ppargc1a), CBP/p300 (Crebbp) and Src1 (Ncoa1) to the PPRE. Our studies thus demonstrate an essential role for Jhdm2a in regulating metabolic gene expression and normal weight control in mice.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4085783/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4085783/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tateishi, Keisuke -- Okada, Yuki -- Kallin, Eric M -- Zhang, Yi -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Apr 9;458(7239):757-61. doi: 10.1038/nature07777. Epub 2009 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19194461" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, Brown/metabolism ; Animals ; Cells, Cultured ; Energy Metabolism/*physiology ; Gene Expression Profiling ; *Gene Expression Regulation ; Glycerol/metabolism ; Ion Channels/metabolism ; Jumonji Domain-Containing Histone Demethylases ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondrial Proteins/metabolism ; Muscle, Skeletal/metabolism ; Obesity/*metabolism ; Oxidation-Reduction ; Oxidoreductases, N-Demethylating/*genetics/*metabolism ; Phenotype ; Receptors, Adrenergic, beta/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    C/EBPalpha poises B cells for rapid reprogramming into induced pluripotent stem cells (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-12-18
    Description: CCAAT/enhancer binding protein-alpha (C/EBPalpha) induces transdifferentiation of B cells into macrophages at high efficiencies and enhances reprogramming into induced pluripotent stem (iPS) cells when co-expressed with the transcription factors Oct4 (Pou5f1), Sox2, Klf4 and Myc (hereafter called OSKM). However, how C/EBPalpha accomplishes these effects is unclear. Here we find that in mouse primary B cells transient C/EBPalpha expression followed by OSKM activation induces a 100-fold increase in iPS cell reprogramming efficiency, involving 95% of the population. During this conversion, pluripotency and epithelial-mesenchymal transition genes become markedly upregulated, and 60% of the cells express Oct4 within 2 days. C/EBPalpha acts as a 'path-breaker' as it transiently makes the chromatin of pluripotency genes more accessible to DNase I. C/EBPalpha also induces the expression of the dioxygenase Tet2 and promotes its translocation to the nucleus where it binds to regulatory regions of pluripotency genes that become demethylated after OSKM induction. In line with these findings, overexpression of Tet2 enhances OSKM-induced B-cell reprogramming. Because the enzyme is also required for efficient C/EBPalpha-induced immune cell conversion, our data indicate that Tet2 provides a mechanistic link between iPS cell reprogramming and B-cell transdifferentiation. The rapid iPS reprogramming approach described here should help to fully elucidate the process and has potential clinical applications.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Di Stefano, Bruno -- Sardina, Jose Luis -- van Oevelen, Chris -- Collombet, Samuel -- Kallin, Eric M -- Vicent, Guillermo P -- Lu, Jun -- Thieffry, Denis -- Beato, Miguel -- Graf, Thomas -- England -- Nature. 2014 Feb 13;506(7487):235-9. doi: 10.1038/nature12885. Epub 2013 Dec 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Gene Regulation, Stem Cells and Cancer Programme, Centre for Genomic Regulation (CRG), Dr Aiguader 88, 08003 Barcelona, Spain [2] Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain. ; 1] Gene Regulation, Stem Cells and Cancer Programme, Centre for Genomic Regulation (CRG), Dr Aiguader 88, 08003 Barcelona, Spain [2] Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain [3]. ; 1] Ecole Normale Superieure, Institut de Biologie de l'ENS, 45 Rue d'Ulm, Paris F-75005, France [2] Inserm, U1024, Paris F-75005, France [3] CNRS, UMR 8197, Paris F-75005, France. ; 1] Gene Regulation, Stem Cells and Cancer Programme, Centre for Genomic Regulation (CRG), Dr Aiguader 88, 08003 Barcelona, Spain [2] Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain [3] Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, USA. ; Yale Cancer Center, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA. ; 1] Gene Regulation, Stem Cells and Cancer Programme, Centre for Genomic Regulation (CRG), Dr Aiguader 88, 08003 Barcelona, Spain [2] Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain [3] Institucio Catalana de Recerca i Estudis Avancats (ICREA), Pg Lluis Companys 23, 08010 Barcelona, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24336202" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/*cytology/*metabolism ; CCAAT-Enhancer-Binding Protein-alpha/genetics/*metabolism ; *Cell Transdifferentiation ; Cells, Cultured ; *Cellular Reprogramming/genetics ; Chromatin/genetics/metabolism ; Cytosine/metabolism ; DNA Methylation ; DNA-Binding Proteins/genetics/metabolism ; Deoxyribonuclease I/metabolism ; Epithelial-Mesenchymal Transition/genetics ; Induced Pluripotent Stem Cells/*cytology/*metabolism ; Kruppel-Like Transcription Factors/genetics/metabolism ; Mice ; Octamer Transcription Factor-3/genetics/metabolism ; Proto-Oncogene Proteins/genetics/metabolism ; Proto-Oncogene Proteins c-myc/genetics/metabolism ; SOXB1 Transcription Factors/genetics/metabolism ; Up-Regulation/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Pre-B cell to macrophage transdifferentiation without significant promoter DNA methylation changes (2012)
    Oxford University Press
    Details
    Publication Date: 2012-03-14
    Description: Transcription factor-induced lineage reprogramming or transdifferentiation experiments are essential for understanding the plasticity of differentiated cells. These experiments helped to define the specific role of transcription factors in conferring cell identity and played a key role in the development of the regenerative medicine field. We here investigated the acquisition of DNA methylation changes during C/EBPα-induced pre-B cell to macrophage transdifferentiation. Unexpectedly, cell lineage conversion occurred without significant changes in DNA methylation not only in key B cell- and macrophage-specific genes but also throughout the entire set of genes differentially methylated between the two parental cell types. In contrast, active and repressive histone modification marks changed according to the expression levels of these genes. We also demonstrated that C/EBPα and RNA Pol II are associated with the methylated promoters of macrophage-specific genes in reprogrammed macrophages without inducing methylation changes. Our findings not only provide insights about the extent and hierarchy of epigenetic events in pre-B cell to macrophage transdifferentiation but also show an important difference to reprogramming towards pluripotency where promoter DNA demethylation plays a pivotal role.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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