CARM1 is required in embryonic stem cells to maintain pluripotency and resist differentiation.
Histone H3 methylation at R17 and R26 recently emerged as a novel epigenetic mechanism regulating pluripotency in mouse embryos. Blastomeres of four-cell embryos with high H3 methylation at these sites show unrestricted potential, whereas those with lower levels cannot support development when aggregated in chimeras of like cells. Increasing histone H3 methylation, through expression of coactivator-associated-protein-arginine-methyltransferase 1 (CARM1) in embryos, elevates expression of key pluripotency genes and directs cells to the pluripotent inner cell mass. We demonstrate CARM1 is also required for the self-renewal and pluripotency of embryonic stem (ES) cells. In ES cells, CARM1 depletion downregulates pluripotency genes leading to their differentiation. CARM1 associates with Oct4/Pou5f1 and Sox2 promoters that display detectable levels of R17/26 histone H3 methylation. In CARM1 overexpressing ES cells, histone H3 arginine methylation is also at the Nanog promoter to which CARM1 now associates. Such cells express Nanog at elevated levels and delay their response to differentiation signals. Thus, like in four-cell embryo blastomeres, histone H3 arginine methylation by CARM1 in ES cells allows epigenetic modulation of pluripotency.
Wu
Qiang
Q
Wellcome Trust and Cancer Research UK Gurdon Institute.|Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
Bruce
Alexander W
AW
Wellcome Trust and Cancer Research UK Gurdon Institute.
Jedrusik
Agnieszka
A
Wellcome Trust and Cancer Research UK Gurdon Institute.
Ellis
Peter D
PD
The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, United Kingdom.
Andrews
Robert M
RM
The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, United Kingdom.
Langford
Cordelia F
CF
The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, United Kingdom.
Glover
David M
DM
Cancer Research UK Cell Cycle Genetics Research Group, University of Cambridge, Department of Genetics, Cambridge, United Kingdom.
Zernicka-Goetz
Magdalena
M
Wellcome Trust and Cancer Research UK Gurdon Institute.|Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
D000818:Animals; D001120:Arginine / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D008745:Methylation; D051379:Mice; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000235:genetics
D006657:Histones; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D001120:Arginine; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1