Aberrant activation of canonical Notch1 signaling in the mouse uterus decreases <i>progesterone receptor</i> by hypermethylation and leads to infertility

Abstract

Significance These studies show a physiological role for Notch signaling in female reproduction. The fact that both loss and gain of function of Notch signaling result in the impairment of early pregnancy identifies Notch1 signaling as a critical regulator of endometrial function. We also provide the first evidence, to our knowledge, that Notch signaling can regulate methylation of exon 1 of the progesterone receptor ( Pgr ) gene through its target PU.1, which provides novel insight into the role of Notch in steroid hormone regulation. This mechanism also provides an opportunity for future studies in identifying the cause of progesterone resistance in gynecological pathologies in women, such as endometriosis and adenomyosis, in which the hypermethylation of Pgr has been reported.