The elongation of Mest transcript into MestXL sustains, but does not initiate, the maternal allele bias of its convergent gene Copg2 during neurogenesis
In the authors' words
Abstract Precise gene dosage control is critical for cellular identity and development, particularly for imprinted genes, where dosage imbalances are linked to neurodevelopmental disorders. The Mest/Copg2 imprinted locus exemplifies this fine-tuned regulation: while Mest is constitutively paternally expressed, Copg2 shifts from biallelic to maternally-biased expression specifically during neural differentiation, a transition proposed to involve transcriptional interference by the long Mest isoform, MestXL , which extends into Copg2 . However, the mechanisms underlying this switch and whether factors beyond MestXL contribute remain unresolved. Using a stem cell-based brain organoid model integrating multi-omic analyses, 3D chromatin mapping, and functional approaches, we challenge the prevailing model by showing that the maternal bias of Copg2 is not solely driven by MestXL -mediated interference. Instead, our data reveal a temporal, stage-specific two-step mechanism: putative enhancer-driven activation of the maternal allele in neural progenitors, followed by MestXL -dependent repression of the paternal allele in neuron-enriched stages. This uncovers an unexpected complexity in imprinted gene dosage regulation during brain development.
Appeared: Friday, September 25. Nature Communications. Peer-reviewed journal.