S-sulfhydration of histone variant H3.3 transcriptionally controls the extracellular matrix remodeling gene Adam19 to modulate the FAK-ERK1/2 cascade in granulosa cell to safeguard the ovary against aging in mouse

S-sulfhydration of proteins has been widely reported to be an important event downstream of H2S signaling. In this study, we identified the S-sulfhydration of histone variant H3.3 (sH3.3) in granulosa cells (GCs) and found the level of sH3.3 was negatively correlative with the POI/POF disease, as well as the endogenous H2S level in GCs. By the mouse model, we showed the downregulation of sH3.3 resulted to the deficiency of female fertility and ovarian function. The biological processes, including the cell adhesion, steroid biosynthetic process, blood vessel remodeling, were impaired severely, which led to the ovary aging. Further we demonstrated that the deficient s-sulfhydration directly downregulated the interction of H3.3 to E2F1, which further impaired the E2F1 binding to Adam19 promoter. The downregulated Adam19 attenuated the Integrin-FAK-ERK1/2 signaling that was critical to the granulosa cells. Collectively, our study uncovered the relationship of the endogenous H2S and POI disease in granulosa cells. And for the first time, we detected the critic role of sH3.3 in physiology in granulosa cell and demonstrated the transcriptional regulation role of the persulfhydration of H3.3. mechanically.