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

Nicholas K Vinckier,Ryan J Geusz,Ulupi S Jhala,Allen Wang,Austin R Harrington,Christopher W Benner,Nichole Wetton,Jianxun Wang,Maike Sander,Matthew Wortham,Michael G Rosenfeld,Ileana Matta,Hung-Ping Shih,Jinzhao Wang,Nisha A Patel

doi:10.1038/s41467-020-16017-x

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.

Highlights

Developmental progression depends on temporally defined changes in gene expression mediated by transient exposure of lineage intermediates to signals in the progenitor niche
Given prior findings that Lysine-specific demethylase 1 (LSD1) activity is inhibited in context of acetylated histones[9], these results suggest that histone acetylation from gut tube (GT) to PP1 prevents LSD1-mediated enhancer silencing and that LSD1-independent H3K27 acetylation (H3K27ac) removal allows LSD1 to silence these enhancers during the PP1 to PP2 transition
Our findings show that decommissioning of retinoic acid (RA)-dependent early pancreatic enhancers temporally limits the expression of RAinduced genes after RA is removed, thereby creating a sharp and transient gene expression response to RA

Summary

Introduction

Developmental progression depends on temporally defined changes in gene expression mediated by transient exposure of lineage intermediates to signals in the progenitor niche. 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. Lysine-specific demethylase 1 (LSD1), known as KDM1A, regulates chromatin by catalysing the removal of mono- and dimethyl marks from K4 at histone H37, rendering poised enhancer chromatin inactive[8] This process has been called enhancer decommissioning and is coupled to complete silencing of associated genes[8]. Our results show that loss of LSD1 function critically alters the epigenetic landscape that terminates the competence window for RA signalling These findings identify modification of the epigenome as an important cell-intrinsic mechanism for sharpening transcriptional responses to developmental signals

Methods

Results

Conclusion