The Influence Of Histone Acetyltransferase KAT8 On Mouse Follicle Development

Proper follicle development is critical for female fertility.As follicle development is a complex biological process involves in cell growth,proliferation and differentiation,it requires timely as well as accurate gene expression.Histone acetylation is an important manner for gene regulation.Histone acetyltransferases and histone deacetylases can regulate transcription via affecting chromatin structure by changing the electrostatic affinity between the histone and DNA.K(Lysine)Acetyltransferase 8(KAT8),an important component of the X chromosome dosage compensation system in Drosophila,is a major acetyl transferase for histone H4 at lysine 16.We found that both oocyte and granulosa cell express Kat8,with higher expression levels in nucleus of GV stage oocytes.Then we used conditional knockout mouse models to explore the function of Kat8 during mouse follicle development.The result showed that oocyte Kat8 deletion results in sterile females with follicle development failure in the secondary and preantral follicle stages.More atretic follicles,as well as oocytes undergo apoptosis and serious DNA damages are observed after Kat8 deletion,while the proliferation of granulosa cells is unaffected.In Kat8 deficiency oocytes,decreased H4K16ac levels and abnormal heterochromatin configurations are observed.Expressions of several important antioxidant genes,including Prdxl,Prdx2,Gpx1 and Gpx4,are significantly down-regulated,with a subsequent increase in reactive oxygen species levels after Kat8 deletion in oocytes.The defective follicle and oocyte development observed in oocyte Kat8 deletion mice could be rescued by intraperitoneal injection of N-acetylcysteine,an antioxidant.The levels of reactive oxygen species,DNA damage and apoptosis decrease significantly at the same time after N-acctylcysteine injection.KAT8 can regulate antioxidant gene expression through binding to DNAs directly in the promoter regions.While Kat8 deletion in granulosa cells reveals no effects on follicle development and female fertility.Taken together,our findings demonstrate that KAT8 is essential for female fertility by regulating antioxidant gene expression,which is the first acetyltransferase reported to function in mouse oocyte development so far.Our results also provide scientific evidence for the cure infertility induced by abnormal follicle development.