The elongation of Mest transcript into MestXL sustains, but does not initiate, the maternal allele bias of its convergent gene Copg2 during neurogenesis
Abstract
Precise gene dosage control is critical for establishing cellular identity and development, especially for imprinted genes, where dosage imbalances are linked to severe pathologies such as neurodevelopmental disorders. The Mest/Copg2 imprinted locus is a paradigm for this fine-tuned regulation. While Mest is constitutively expressed from the paternal allele, Copg2 expression shifts from biallelic to a 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, are 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 maternal allele bias throughout neural lineage specification. Our findings challenge the prevailing model by demonstrating that the maternal allele bias of Copg2 during neural differentiation is not solely driven by MestXL -mediated transcriptional interference. Instead, our data support a temporal and neural stage-specific two-step mechanism: putative enhancer-driven activation of the maternal allele in neural progenitor cells is followed by MestXL -dependent repression of the paternal allele in neuron-enriched stages. This uncovers an unexpected layer of complexity in the regulation of imprinted gene dosage during brain development, with profound implications for understanding the molecular underpinnings of neurodevelopmental disorders.
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BibTeX
@misc{perillous2026elongation,
title = {{The elongation of Mest transcript into MestXL sustains, but does not initiate, the maternal allele bias of its convergent gene Copg2 during neurogenesis}},
author = {Sophie Perillous and Anne-Charlotte Fromaget and Céline Gonthier-Guéret and Ornella Clerici and Marion Espenel and Alice Murigneux and Sophie Phan and Lea Feit and Catherine Vaurs-Barriére and Floric Slimani and Céline Lemmers and Davide Normanno and Amanda Ha and Nolan Ashworth and Aaron Bogutz and Hiromi Kamura and Nuttamonpat Gumpangseth and Kenichiro Hata and Bertille Montibus and Kazuhiko Nakabayashi and Louis Lefebvre and Tristan Bouschet and Franck Court and Philippe P. Arnaud},
howpublished = {Nature Communications},
year = {2026},
month = oct,
doi = {10.64898/2026.03.13.711300},
url = {https://hal.science/hal-05769836v2},
note = {CC BY-NC 4.0},
}
RIS
TY - UNPB
TI - The elongation of Mest transcript into MestXL sustains, but does not initiate, the maternal allele bias of its convergent gene Copg2 during neurogenesis
AU - Sophie Perillous
AU - Anne-Charlotte Fromaget
AU - Céline Gonthier-Guéret
AU - Ornella Clerici
AU - Marion Espenel
AU - Alice Murigneux
AU - Sophie Phan
AU - Lea Feit
AU - Catherine Vaurs-Barriére
AU - Floric Slimani
AU - Céline Lemmers
AU - Davide Normanno
AU - Amanda Ha
AU - Nolan Ashworth
AU - Aaron Bogutz
AU - Hiromi Kamura
AU - Nuttamonpat Gumpangseth
AU - Kenichiro Hata
AU - Bertille Montibus
AU - Kazuhiko Nakabayashi
AU - Louis Lefebvre
AU - Tristan Bouschet
AU - Franck Court
AU - Philippe P. Arnaud
PY - 2026
DA - 2026/10/26
PB - Nature Communications
DO - 10.64898/2026.03.13.711300
UR - https://hal.science/hal-05769836v2
AB - Precise gene dosage control is critical for establishing cellular identity and development, especially for imprinted genes, where dosage imbalances are linked to severe pathologies such as neurodevelopmental disorders. The Mest/Copg2 imprinted locus is a paradigm for this fine-tuned regulation. While Mest is constitutively expressed from the paternal allele, Copg2 expression shifts from biallelic to a 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, are 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 maternal allele bias throughout neural lineage specification. Our findings challenge the prevailing model by demonstrating that the maternal allele bias of Copg2 during neural differentiation is not solely driven by MestXL -mediated transcriptional interference. Instead, our data support a temporal and neural stage-specific two-step mechanism: putative enhancer-driven activation of the maternal allele in neural progenitor cells is followed by MestXL -dependent repression of the paternal allele in neuron-enriched stages. This uncovers an unexpected layer of complexity in the regulation of imprinted gene dosage during brain development, with profound implications for understanding the molecular underpinnings of neurodevelopmental disorders.
SN - 2041-1723
SN - 2041-1723
ER -