Direct regulation of genes involved in sperm release by estrogen and androgen through their receptors and coregulators

- Actin remodeling-related genes (Arpc1b, Evl) have a functional estrogen response element.
- Endocytosis-related genes (Picalm, Eea1, and Stx5a) have a functional androgen response element.
- Estrogen regulates Arpc1b and Evl expression through ER beta via NCoR1 and Src1, respectively.
- Androgen regulates Picalm and Eea1 expression via NCoR1 and Stx5a expression via Src1.
- Estrogen regulates actin remodeling, whereas androgen regulates endocytosis during sperm release.

Steroid hormones, estrogen and androgen, control transcription in various reproductive and non-reproductive tissues. Both hormones are known to be important for control of sperm release from the seminiferous epithelium (spermiation), a process characterized by extensive remodeling of actin filaments and endocytosis. Earlier studies with an estrogen (E2)-induced rat model of spermiation failure revealed genes involved in actin remodeling (Arpc1b and Evl) and endocytosis (Picalm, Eea1, and Stx5a) to be differentially regulated. Further, among these genes, Arpc1b and Evl were found to be estrogen-responsive whereas Eea1 and Stx5a were androgen-responsive and Picalm was responsive to both hormones in seminiferous tubule cultures. Yet, the mechanism by which these genes are regulated by estrogen and androgen in the testis was unclear. Here, we report the presence of a functional estrogen response element (ERE) upstream of Arpc1b and Evl genes and androgen response element (ARE) upstream of Picalm, Eea1, and Stx5a genes. Chromatin immunoprecipitation in control versus E2-treated testes revealed significant changes in estrogen receptor beta (ERβ) recruitment along with coregulators to the EREs upstream of Arpc1b and Evl genes and androgen receptor (AR) at AREs upstream of Picalm, Eea1, and Stx5a genes. Enrichment patterns of these EREs/AREs with coregulators, activating and repressing histone modifications along with RNA polymerase II recruitment, correlated with the observed expression patterns of these genes upon E2 treatment. Taken together, our results reveal direct targets of estrogen and androgen in the testes and provide insights into transcriptional control of sperm release by the two steroid hormones.