The SMARCA5–DMRT1 Pioneer Complex Establishes Epigenetic Priming to Direct Male Germline Development

TL;DR

This paper shows how the SMARCA5–DMRT1 complex prepares male germ cells to respond to retinoic acid, enabling their development into sperm.

Contribution

The study reveals a novel mechanism where SMARCA5 and DMRT1 establish chromatin accessibility for retinoic acid signaling in male germline development.

Findings

SMARCA5 is essential for retinoic acid-induced differentiation in male germ cells.

The SMARCA5–DMRT1 complex creates chromatin accessibility at germline gene loci.

This complex enables RA receptor binding and transcriptional responses in spermatogenesis.

Abstract

The establishment of cell type–specific chromatin landscapes is essential for cellular identity, but how these landscapes are generated remains poorly understood. Here, we demonstrate that the chromatin remodeler SMARCA5 establishes epigenetic priming that is required for retinoic acid (RA)–induced differentiation in the male germline. Germ cell–specific deletion of Smarca5 results in a complete loss of differentiating spermatogonia, phenocopying vitamin A-deficient mice that lack RA signaling. During the perinatal transition from prospermatogonia to undifferentiated spermatogonia, SMARCA5 is recruited to binding sites of the transcription factor DMRT1, which are located at distal putative enhancers and promoters of germline genes. The SMARCA5–DMRT1 pioneer complex establishes chromatin accessibility at these loci, generating poised enhancers and promoters that serve as RA receptor (RAR)–binding sites. Thus, SMARCA5 licenses transcriptional responses to RA that enable spermatogenic differentiation. Our findings uncover a mechanism linking pioneer factor activity to external signal responsiveness.

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