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

Nicholas K. Vinckier, Nisha A. Patel, Ryan J. Geusz, Allen Wang, Jinzhao Wang, Ileana Matta, Austin R. Harrington, Matthew Wortham, Nichole Wetton, Jianxun Wang, Ulupi S. Jhala, Michael G. Rosenfeld, Christopher W. Benner, Hung-Ping Shih and Maike Sander ()
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Nicholas K. Vinckier: University of California, San Diego
Nisha A. Patel: University of California, San Diego
Ryan J. Geusz: University of California, San Diego
Allen Wang: University of California, San Diego
Jinzhao Wang: University of California, San Diego
Ileana Matta: University of California, San Diego
Austin R. Harrington: University of California, San Diego
Matthew Wortham: University of California, San Diego
Nichole Wetton: University of California, San Diego
Jianxun Wang: University of California, San Diego
Ulupi S. Jhala: University of California, San Diego
Michael G. Rosenfeld: University of California, San Diego
Christopher W. Benner: University of California, San Diego
Hung-Ping Shih: Diabetes & Metabolism Research Institute, City of Hope
Maike Sander: University of California, San Diego

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16017-x

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