BRD8 deficiency leads to progressive impairment of spermatogenesis in mice.

Abstract

BRD8, a member of the bromodomain-containing protein family, is a chromatin-associated protein that recognizes acetylated histones and recruits regulatory factors to modulate gene expression. Despite extensive studies of BRD8 in tumor biology, its physiological roles in normal tissues remain largely unknown. Given its enriched expression in the testis, we investigated the role of Brd8 in male reproduction using a germ cell-specific Brd8 knockout mouse model. Brd8 deficiency resulted in a marked reduction in testicular size and sperm counts, accompanied by severe defects in germ cell differentiation. Immunofluorescence staining for germ cell markers demonstrated progressive spermatogenic defects, with a reduction in spermatids followed by declines in spermatocytes and spermatogonia at later ages. Single-cell transcriptome analysis of Brd8-knockout testes revealed transcriptional alterations in spermatogonia and spermatocytes, including dysregulation of translation-related pathways and reduced expression of genes involved in meiotic progression. In addition, VEGF-related signaling within the endothelial compartment was reduced in Brd8-knockout testes, suggesting secondary remodeling of the testicular microenvironment associated with progressive germ cell dysfunction. Our findings provide new insights into the role of BRD8, an epigenetic reader, in male fertility.