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).
Faithful chromosome segregation in oocytes relies on the precise coordination of core centromeric chromatin, dynamic kinetochore assembly, and spindle interactions. In meiosis I, sister kinetochores are mono-oriented toward the same spindle pole, allowing homologous chromosomes to bi-orient and segregate properly, whereas meiosis II exhibits conventional bi-orientation of sister chromatids. Stepwise assembly of kinetochore subcomplexes, Meikin-mediated mono-orientation, and protection of centromeric cohesion by Shugoshin ensure accurate segregation through meiotic divisions. These same structural and regulatory features, however, are also exploited by selfish centromeres to bias chromosome orientation on the oocyte spindle, leading to biased segregation to the egg and therefore to the next generation in violation of Mendel's Law of Segregation. We will review recent studies that have established a mechanistic framework for both accurate chromosome segregation and non-Mendelian segregation in oocytes, highlighting the central role of meiotic centromeres in female reproduction and evolutionary conflict.
