The regulation of Tet1 by steroidhormones in proliferating gonadotrope precursor cells
The hydroxymethylase, Tet1, plays amajor role in regulating gene expression, and its knockdown specificallyaffects fertility. Reproductive function is activated by hormones produced ingonadotrope cells of the pituitary gland, which are tightly controlled by thegonadal steroids. We found that Tet1 is expressed in proliferatinggonadotrope precursor cells, but is down-regulated to allow their maturation,and hypothesized that gonadal steroids might be responsible for thisrepression. Exposure to androgens or estrogens inhibited Tet1 expressionand we have demonstrated two distinct mechanisms. First, the steroid receptorsbind several regulatory regions upstream of Tet1 and induce changes tothe chromatin structure and histone modifications to hinder Tet1transcription initiation. In addition, estradiol lowers Tet1 mRNAstability by decreasing the m6A methylation. Asides from playing a crucial rolein the central control of reproduction, the regulationof Tet1 expression by gonadal steroid hormones has implications in the context of cell proliferationand differentiation in other steroid-responsive tissues, includingsteroid-dependent cancers.