The histone chaperone CAF-1 safeguards somatic cell identity

Sihem Cheloufi, Ulrich Elling, Barbara Hopfgartner, Youngsook L. Jung, Jernej Murn, Maria Ninova, Maria Hubmann, Aimee I. Badeaux, Cheen Euong Ang, Danielle Tenen, Daniel J. Wesche, Nadezhda Abazova, Max Hogue, Nilgun Tasdemir, Justin Brumbaugh, Philipp Rathert, Julian Jude, Francesco Ferrari, Andres Blanco, Michaela Fellner, Daniel Wenzel, Marietta Zinner, Simon E. Vidal, Oliver Bell, Matthias Stadtfeld, Howard Y. Chang, Genevieve Almouzni, Scott W. Lowe, John Rinn, Marius Wernig, Alexei Aravin, Yang Shi, Peter J. Park, Josef M. Penninger, Johannes Zuber () and Konrad Hochedlinger ()
Additional contact information
Sihem Cheloufi: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital
Ulrich Elling: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)
Barbara Hopfgartner: Research Institute of Molecular Pathology (IMP)
Youngsook L. Jung: Harvard Medical School
Jernej Murn: Harvard Medical School
Maria Ninova: California Institute of Technology
Maria Hubmann: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)
Aimee I. Badeaux: Harvard Medical School
Cheen Euong Ang: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University
Danielle Tenen: Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute
Daniel J. Wesche: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital
Nadezhda Abazova: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital
Max Hogue: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital
Nilgun Tasdemir: Memorial Sloan Kettering Cancer Center
Justin Brumbaugh: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital
Philipp Rathert: Research Institute of Molecular Pathology (IMP)
Julian Jude: Research Institute of Molecular Pathology (IMP)
Francesco Ferrari: Harvard Medical School
Andres Blanco: Harvard Medical School
Michaela Fellner: Research Institute of Molecular Pathology (IMP)
Daniel Wenzel: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)
Marietta Zinner: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)
Simon E. Vidal: The Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, NYU School of Medicine
Oliver Bell: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)
Matthias Stadtfeld: The Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, NYU School of Medicine
Howard Y. Chang: Howard Hughes Medical Institute
Genevieve Almouzni: Centre de Recherche, Institut Curie
Scott W. Lowe: Howard Hughes Medical Institute
John Rinn: Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute
Marius Wernig: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University
Alexei Aravin: California Institute of Technology
Yang Shi: Harvard Medical School
Peter J. Park: Harvard Medical School
Josef M. Penninger: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)
Johannes Zuber: Research Institute of Molecular Pathology (IMP)
Konrad Hochedlinger: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital

Nature, 2015, vol. 528, issue 7581, 218-224

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature15749

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