Publication Date:
2015-12-15
Description:
Cellular differentiation involves profound remodelling of chromatic landscapes, yet the mechanisms by which somatic cell identity is subsequently maintained remain incompletely understood. To further elucidate regulatory pathways that safeguard the somatic state, we performed two comprehensive RNA interference (RNAi) screens targeting chromatin factors during transcription-factor-mediated reprogramming of mouse fibroblasts to induced pluripotent stem cells (iPS cells). Subunits of the chromatin assembly factor-1 (CAF-1) complex, including Chaf1a and Chaf1b, emerged as the most prominent hits from both screens, followed by modulators of lysine sumoylation and heterochromatin maintenance. Optimal modulation of both CAF-1 and transcription factor levels increased reprogramming efficiency by several orders of magnitude and facilitated iPS cell formation in as little as 4 days. Mechanistically, CAF-1 suppression led to a more accessible chromatin structure at enhancer elements early during reprogramming. These changes were accompanied by a decrease in somatic heterochromatin domains, increased binding of Sox2 to pluripotency-specific targets and activation of associated genes. Notably, suppression of CAF-1 also enhanced the direct conversion of B cells into macrophages and fibroblasts into neurons. Together, our findings reveal the histone chaperone CAF-1 to be a novel regulator of somatic cell identity during transcription-factor-induced cell-fate transitions and provide a potential strategy to modulate cellular plasticity in a regenerative setting.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cheloufi, Sihem -- Elling, Ulrich -- Hopfgartner, Barbara -- Jung, Youngsook L -- Murn, Jernej -- Ninova, Maria -- Hubmann, Maria -- Badeaux, Aimee I -- Euong Ang, Cheen -- Tenen, Danielle -- Wesche, Daniel J -- Abazova, Nadezhda -- Hogue, Max -- Tasdemir, Nilgun -- Brumbaugh, Justin -- Rathert, Philipp -- Jude, Julian -- Ferrari, Francesco -- Blanco, Andres -- Fellner, Michaela -- Wenzel, Daniel -- Zinner, Marietta -- Vidal, Simon E -- Bell, Oliver -- Stadtfeld, Matthias -- Chang, Howard Y -- Almouzni, Genevieve -- Lowe, Scott W -- Rinn, John -- Wernig, Marius -- Aravin, Alexei -- Shi, Yang -- Park, Peter J -- Penninger, Josef M -- Zuber, Johannes -- Hochedlinger, Konrad -- P50-HG007735/HG/NHGRI NIH HHS/ -- R01 HD058013-06/HD/NICHD NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Dec 10;528(7581):218-24. doi: 10.1038/nature15749.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA. ; Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA. ; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), A-1030 Vienna, Austria. ; Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), A-1030 Vienna, Austria. ; Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts 02115, USA. ; California Institute of Technology, Division of Biology and Biological Engineering, Pasadena, California 91125, USA. ; Institute for Stem Cell Biology and Regenerative Medicine, Department of Pathology and Department of Bioengineering, Stanford University, Stanford, California 94305, USA. ; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA. ; Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; The Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, Department of Cell Biology, NYU School of Medicine, New York, New York 10016, USA. ; Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA. ; Centre de Recherche, Institut Curie, 75248 Paris, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26659182" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cells, Cultured
;
Cellular Reprogramming/*genetics
;
Chromatin/metabolism
;
Chromatin Assembly Factor-1/antagonists & inhibitors/genetics/*metabolism
;
Gene Expression Regulation/genetics
;
Heterochromatin/metabolism
;
Mice
;
Nucleosomes/metabolism
;
RNA Interference
;
Transduction, Genetic
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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