SALL1 Is an Orchestrator of Uterine Receptivity in Part via Titration of Estrogen Signaling

SALL1 is a critical regulator of embryonic development across a wide swath of tissues, including vital organs, but little is known about its function in adult tissues. Recent work from our group demonstrates that SALL1 is involved in urogenital development. This study delineates the role of SALL1 transcription factor in the adult reproductive system by demonstrating its requirement at multiple levels of uterine function during the implantation phase of early pregnancy. By generating a conditional knockout mouse model of Sall1 exclusively in female reproductive organs, it is demonstrated here that SALL1 is independently required both in the uterine luminal epithelium for the attachment of competent blastocysts to the uterine wall and in the uterine stroma for the process of decidualization, another prerequisite for pregnancy success. This robust, multitissue-layer requirement for SALL1 across multiple stages in the process of implantation makes it a newly identified regulator of early pregnancy. Here, it is shown that loss of SALL1 causes misexpression of estrogen receptor α during the window of implantation, and subsequent pathological deregulation of multiple estrogen response genes whose tight titrations are prerequisites of pregnancy. RNA sequencing of independent knockout uterine compartments at multiple timepoints, and chromatin immunoprecipitation sequencing to identify direct transcriptional targets, elucidated multiple powerful regulatory pathways downstream of SALL1. Importantly, the use of a selective estrogen receptor antagonist, fulvestrant, at a precise timepoint and dose, offers a partial rescue of embryo attachment to the uterine luminal epithelium, further demonstrating that SALL1 is upstream of estrogen receptor α during implantation phase signaling.