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LSD1-mediated enhancer silencing attenuates retinoic acid signalling during pancreatic endocrine cell development

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Item Type:Article
Title:LSD1-mediated enhancer silencing attenuates retinoic acid signalling during pancreatic endocrine cell development
Creators Name:Vinckier, N.K. and Patel, N.A. and Geusz, R.J. and Wang, A. and Wang, J. and Matta, I. and Harrington, A.R. and Wortham, M. and Wetton, N. and Wang, J. and Jhala, U.S. and Rosenfeld, M.G. and Benner, C.W. and Shih, H.P. and Sander, M.
Abstract:Developmental progression depends on temporally defined changes in gene expression mediated by transient exposure of lineage intermediates to signals in the progenitor niche. To determine whether cell-intrinsic epigenetic mechanisms contribute to signal-induced transcriptional responses, here we manipulate the signalling environment and activity of the histone demethylase LSD1 during differentiation of hESC-gut tube intermediates into pancreatic endocrine cells. We identify a transient requirement for LSD1 in endocrine cell differentiation spanning a short time-window early in pancreas development, a phenotype we reproduced in mice. Examination of enhancer and transcriptome landscapes revealed that LSD1 silences transiently active retinoic acid (RA)-induced enhancers and their target genes. Furthermore, prolonged RA exposure phenocopies LSD1 inhibition, suggesting that LSD1 regulates endocrine cell differentiation by limiting the duration of RA signalling. Our findings identify LSD1-mediated enhancer silencing as a cell-intrinsic epigenetic feedback mechanism by which the duration of the transcriptional response to a developmental signal is limited.
Keywords:Base Sequence, Cell Differentiation, Developmental Gene Expression Regulation, Endocrine Cells, Gene Silencing, Genetic Enhancer Elements, Histone Demethylases, Human Embryonic Stem Cells, Islets of Langerhans, Signal Transduction, Transcription Factors, Tretinoin, Animals, Mice
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:2082
Date:29 April 2020
Official Publication:https://doi.org/10.1038/s41467-020-16017-x
PubMed:View item in PubMed

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