The Fragile X mental retardation protein (FMRP) coordinates an epigenetic checkpoint in neural progenitor cells

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by silencing of the FMR1 gene, which encodes the multifunctional RNA-binding protein FMRP. While FMRP is best known for its roles in RNA metabolism, it can also associate with chromatin through recognition of histone H3 lysine 79 di-methylation (H3K79me2), an epigenetic mark linked to transcriptionally active genes. However, the functional relevance of this FMRP-H3K79me2 interaction has remained largely unexplored in the context of FXS pathophysiology. We assessed H3K79me2 levels during the differentiation of induced pluripotent stem cells generated from both healthy individuals and FXS patients and discovered a global increase in H3K79me2 levels specifically in FXS neural progenitor cells (NPCs). Altered H3K79me2 landscape drives widespread transcriptional dysregulation, marked by reduced expression of neurogenesis-associated genes and aberrant upregulation of programs promoting proliferation and glial lineage commitment. Functionally, these alterations result in enhanced NPC proliferation and a biased differentiation trajectory. Together, our findings uncover an H3K79me2-dependent epigenetic checkpoint that governs NPC proliferation and lineage commitment. We further establish FMRP as a critical component of this checkpoint, linking its loss to the neurodevelopmental defects characteristic of FXS.