Mest transcript elongation to Mestxl sustains, but does not initiate, maternal allele bias of the convergent gene Copg2 in neural differentiation (Region capture Hi-C)

The Mest/Copg2 imprinted locus serves as a paradigm for this fine-tuned regulation. While Mest is constitutively expressed from the paternal allele, Copg2 expression shifts from biallelic to maternal allele bias specifically during neural differentiation, a transition proposed to involve transcriptional interference mediated by the long Mest isoform, Mestxl, which extends into the Copg2 locus.

However, the mechanisms underlying this allelic switch, and whether factors beyond Mestxl contribute, have remained elusive. To address this, we employed a stem cell-based brain organoid model, integrating multi-omic analyses, 3D chromatin structure mapping, and functional approaches to dissect the regulatory events governing the induction and maintenance of Copg2’s maternal allele bias throughout neural lineage specification.