The histone chaperone CAF-1 safeguards somatic cell identity Journal Article

Authors: Cheloufi, S.; Elling, U.; Hopfgartner, B.; Jung, Y. L.; Murn, J.; Ninova, M.; Hubmann, M.; Badeaux, A. I.; Euong, Ang, C.; Tenen, D.; Wesche, D. J.; Abazova, N.; Hogue, M.; Tasdemir, N.; Brumbaugh, J.; Rathert, P.; Jude, J.; Ferrari, F.; Blanco, A.; Fellner, M.; Wenzel, D.; Zinner, M.; Vidal, S. E.; Bell, O.; Stadtfeld, M.; Chang, H. Y.; Almouzni, G.; Lowe, S. W.; Rinn, J.; Wernig, M.; Aravin, A.; Shi, Y.; Park, P. J.; Penninger, J. M.; Zuber, J.; Hochedlinger, K.
Article Title: The histone chaperone CAF-1 safeguards somatic cell identity
Abstract: 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. © 2015 Macmillan Publishers Limited. All rights reserved.
Keywords: controlled study; unclassified drug; nonhuman; animal cell; mouse; somatic cell; protein binding; cell fate; rna interference; cell differentiation; b lymphocyte; fibroblast; pluripotent stem cell; ips; macrophage; nerve cell; transcription factor sox2; heterochromatin; nuclear reprogramming; chromatin structure; enhancer region; chromatin assembly factor 1; priority journal; article; chromatin assembly factor 1a; chromatin assembly factor 1b
Journal Title: Nature
Volume: 528
Issue: 7581
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2015-12-10
Start Page: 218
End Page: 224
Language: English
DOI: 10.1038/nature15749
PROVIDER: scopus
PUBMED: 26659182
PMCID: PMC4866648
Notes: Article -- Export Date: 7 January 2016 -- 218 -- Source: Scopus
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  1. Scott W Lowe
    145 Lowe