title: MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency.
abstract: The chromatin template imposes an epigenetic barrier during the process of somatic cell reprogramming. Using fibroblasts derived from macroH2A double knockout (dKO) mice, here we show that these histone variants act cooperatively as a barrier to induced pluripotency. Through manipulation of macroH2A isoforms, we further demonstrate that macroH2A2 is the predominant barrier to reprogramming. Genomic analyses reveal that macroH2A1 and macroH2A2, together with H3K27me3, co-occupy pluripotency genes in wild-type (wt) fibroblasts. In particular, we find macroH2A isoforms to be highly enriched at target genes of the K27me3 demethylase, Utx, which are reactivated early in iPS reprogramming. Finally, while macroH2A dKO-induced pluripotent cells are able to differentiate properly in vitro and in vivo, such differentiated cells retain the ability to return to a stem-like state. Therefore, we propose that macroH2A isoforms provide a redundant silencing layer or terminal differentiation 'lock' at critical pluripotency genes that presents as an epigenetic barrier when differentiated cells are challenged to reprogram.
authors: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA.
authors: Alexandre
authors: A
authors: Gaspar-Maia
authors: Zulekha A
authors: ZA
authors: Qadeer
authors: Dan
authors: D
authors: Hasson
authors: Kajan
authors: K
authors: Ratnakumar
authors: N Adrian
authors: NA
authors: Leu
authors: Gary
authors: G
authors: Leroy
authors: Shichong
authors: S
authors: Liu
authors: Carl
authors: C
authors: Costanzi
authors: David
authors: D
authors: Valle-Garcia
authors: Christoph
authors: C
authors: Schaniel
authors: Ihor
authors: I
authors: Lemischka
authors: Benjamin
authors: B
authors: Garcia
authors: John R
authors: JR
authors: Pehrson
authors: Emily
authors: E
authors: Bernstein
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D065150:Cellular Reprogramming / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism; D020405:Dermis / Q000166:cytology; D058732:Embryoid Bodies / Q000166:cytology / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016678:Genome / Q000235:genetics; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D002843:Chromatin; D006657:Histones; C120756:macroH2A histone; D014212:Tretinoin; D056466:Histone Demethylases; C111778:Utx protein, mouse