Follicle-stimulating hormone promotes histone h3 phosphorylation on serine-10

FSH promoted the rapid phosphorylation of the nuclear protein histone H3 in immature rat ovarian granulosa cells under experimental conditions that le ad to cellular differentiation and not proliferation. FSH-stimulated histon e H3 phosphorylation correlated with cAMP-dependent protein kinase A (PKA) activation and translocation of the PKA catalytic subunit to a nuclear-enri ched fraction and was inhibited by the PKA inhibitor H89, and histone H3 ph osphorylation was stimulated in cells treated with agents that raise intrac ellular cAMP levels such as forskolin and 3-bromo-cAMP. FSH-stimulated hist one H3 phosphorylation in granulosa cells mapped to ser-10, a site previous ly identified as the PKA phosphorylation site in various mitotically active cells as the mitosis-specific phosphorylation site. Injection of the FSH a nalog PMSG to immature rats, which is known to stimulate granulosa cell pro liferation as well as differentiation, also promoted histone H3 phosphoryla tion on ser-10 in granulosa cells, These results establish that FSH-stimula ted histone H3 phosphorylation in granulosa cells is linked not only to gra nulosa cell mitosis but also to granulosa cell differentiation and that FSH -stimulated histone H3 phosphorylation on ser-10 in isolated granulosa cell s is mediated by PKA, These results also identify the PKA-dependent histone H3 phosphorylation as an early nuclear protein marker for FSH-stimulated d ifferentiation of granulosa cells. Based on the recently described function of histone H3 as a coactivator of transcription, these results are consist ent with the hypothesis that phosphorylated histone H3 may facilitate PKA-d ependent gene transcription in granulosa cells leading to the preovulatory phenotype.