Chromatin-Based Control of Mammalian Sex Determination: Integrating Epigenetic and Metabolic Mechanisms

Recent studies have demonstrated that mammalian sex determination is governed not only by trans-acting transcription factors but also by cis-acting chromatin modifications. This review summarizes recent advances in understanding how histone and DNA modifications contribute to sex determination, including the precise temporal regulation of the Y-linked testis-determining gene Sry. Key chromatin regulators—such as KDM3A, EHMT1/2, TET2, CBP/p300, KDM6B, CBX2, and CDYL—shape the chromatin landscape to promote male fate. We also highlight the emerging role of iron metabolism in modulating the activity of chromatin-modifying enzymes, thereby linking cellular metabolic state to epigenetic regulation. Together, these findings underscore the critical role of epigenetic fine-tuning in ensuring proper sex determination and may provide novel insights into the etiology of human disorders of sex development (DSDs).