NEUROD1 reinforces endocrine cell fate acquisition in pancreatic development. Bohuslavova R, Fabriciova V, Smolik O, Lebrón-Mora L, Abaffy P, Benesova S, Zucha D, Valihrach L, Berkova Z, Saudek F, Pavlinkova G. Nat Commun. 2023 Sep 9;14(1):5554. doi: 10.1038/s41467-023-41306-6.
NEUROD1 is a transcription factor that helps maintain a mature phenotype of pancreatic β cells. Disruption of Neurod1 during pancreatic development causes severe neonatal diabetes; however, the exact role of NEUROD1 in the differentiation programs of endocrine cells is unknown. Here, we report a crucial role of the NEUROD1 regulatory network in endocrine lineage commitment and differentiation. Mechanistically, transcriptome and chromatin landscape analyses demonstrate that Neurod1 inactivation triggers a downregulation of endocrine differentiation transcription factors and upregulation of non-endocrine genes within the Neurod1-deficient endocrine cell population, disturbing endocrine identity acquisition. Neurod1 deficiency altered the H3K27me3 histone modification pattern in promoter regions of differentially expressed genes, which resulted in gene regulatory network changes in the differentiation pathway of endocrine cells, compromising endocrine cell potential, differentiation, and functional properties.
Our study reveals dysregulated transcriptome and altered histone methylation patterns in Neurod1ST endocrine cells. Compared to the Control islets of Langerhans, the Neurod1ST endocrine cells exhibit reduced expression of endocrine-related genes and enrichment of non-endocrine genes associated with the exocrine system and pancreatic ductal cells. These findings emphasize the critical role of NEUROD1 in governing gene networks that determine the commitment and terminal differentiation of endocrine cells in the pancreas.