Sin3a is essential for the genome integrity and viability of pluripotent cells.
The Sin3a/HDAC co-repressor complex is a critical regulator of transcription networks that govern cell cycle control and apoptosis throughout development. Previous studies have identified Sin3a as essential for embryonic development around the time of implantation, during which the epiblast cell cycle is uniquely structured to achieve very rapid divisions with little tolerance of DNA damage. This study investigates the specific requirement for Sin3a in the early mouse embryo and shows that embryos lacking Sin3a suffer unresolved DNA damage and acute p53-independent apoptosis specifically in the E3.5-4.5 epiblast. Surprisingly, Myc and E2F targets in Sin3a-null ICMs are downregulated, suggesting a central but non-canonical role for Sin3a in regulating the pluripotent embryonic cell cycle. ES cells deleted for Sin3a mount a DNA damage response indicative of unresolved double-strand breaks, profoundly arrest at G2, and undergo apoptosis. These results indicate that Sin3a protects the genomic integrity of pluripotent embryonic cells and governs their unusual cell cycle.
Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
Patrick
P
McDonel
Jeroen
J
Demmers
David W M
DW
Tan
Fiona
F
Watt
Brian D
BD
Hendrich
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D004249:DNA Damage; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D016195:G2 Phase / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D042822:Genomic Instability / Q000235:genetics*; D005855:Germ Layers / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056264:Sin3 Histone Deacetylase and Corepressor Complex
D050684:E2F Transcription Factors; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D056264:Sin3 Histone Deacetylase and Corepressor Complex