Reprogramming the inactive X chromosome: dynamics and insights from the germline.

Germline reprogramming is an essential process that resets the epigenome prior to gamete formation. Primordial germ cells (PGCs), the progenitors of oocytes and spermatozoa, undergo extensive epigenetic remodelling during development, including genome-wide DNA demethylation, histone modification remodelling, and large-scale reorganisation of 3D genome architecture. In female mammals, an additional layer of epigenetic regulation occurs during PGC reprogramming: the reactivation of the inactive X chromosome, namely, X-chromosome reactivation (XCR). Female PGC precursors carry an inactive X chromosome to ensure dosage compensation prior to reprogramming. While X-chromosome inactivation has been extensively studied for decades, XCR has only more recently emerged as a focus of investigation, and its functional importance for germline development and reproduction remains unclear. XCR takes place along PGC differentiation, from early emergence to meiosis, and involves loss of the long non-coding RNA XIST/Xist coating, DNA demethylation at X-linked promoters, and re-expression of X-linked genes from the inactivated X. Sequential molecular events occurring during XCR have been characterised using both in vivo and in vitro approaches in a broad range of mammals from rodents to humans. In recent years, the emergence of low-input and single-cell omics technologies has substantially advanced our understanding of the inactive X-chromosome reactivation in the germline. In this review, we synthetise recent insights into XCR dynamics in mouse, human, and non-human primate PGCs. We discuss the remaining knowledge gaps and the future perspectives in the field of XCR and germline epigenetic reprogramming.