X chromosome inactivation and reactivation as a new therapeutic approach to treat X-linked genetic disorders

In female mammals, X-chromosome inactivation (XCI) equalizes gene dosage between the sexes but also influences the severity of X-linked dominant disorders, including CDKL5 deficiency disorder (CDD, OMIM #300203) and Rett syndrome (RTT, OMIM #312750), by silencing the wild-type allele in approximately 50% of cells. Modulating the stability and reversibility of XCI therefore represents a promising therapeutic strategy for these conditions. XCI regulation relies on epigenetic mechanisms and higher-order nuclear architecture. In this context, the Lamin B receptor (LBR) has emerged as a key factor in the spreading of the long non-coding RNA Xist and in tethering the inactive X chromosome (Xi) to the nuclear periphery. This PhD project investigated the therapeutic potential and mechanistic regulation of XCI through two complementary approaches. First, peptide-mimetic small molecules identified in a reporter-based screen were validated for their ability to modulate Cdkl5/CDKL5 and Mecp2/MECP2 expression in mouse and human neuronal models. Second, LBR function was examined using a novel N-terminal knockout mouse model and embryonic stem cells lacking the RS and Tudor domains. Together, these findings contribute to the understanding of XCI regulation and support the exploration of pharmacological strategies aimed at reactivating the inactive X chromosome.