Stem Cell Proliferation Is Kept in Check by the Chromatin Regulators Kismet/CHD7/CHD8 and Trr/MLL3/4

Louis Gervais,Marius Van Den Beek,Manon Josserand,Jérémy Sallé,Marine Stefanutti,Carolina N Perdigoto,Patricia Skorski,Khallil Mazouni,Owen J Marshall,Andrea H Brand,François Schweisguth,Allison J Bardin

doi:10.1016/j.devcel.2019.04.033

Abstract

SummaryChromatin remodeling accompanies differentiation, however, its role in self-renewal is less well understood. We report that in Drosophila, the chromatin remodeler Kismet/CHD7/CHD8 limits intestinal stem cell (ISC) number and proliferation without affecting differentiation. Stem-cell-specific whole-genome profiling of Kismet revealed its enrichment at transcriptionally active regions bound by RNA polymerase II and Brahma, its recruitment to the transcription start site of activated genes and developmental enhancers and its depletion from regions bound by Polycomb, Histone H1, and heterochromatin Protein 1. We demonstrate that the Trithorax-related/MLL3/4 chromatin modifier regulates ISC proliferation, colocalizes extensively with Kismet throughout the ISC genome, and co-regulates genes in ISCs, including Cbl, a negative regulator of Epidermal Growth Factor Receptor (EGFR). Loss of kismet or trr leads to elevated levels of EGFR protein and signaling, thereby promoting ISC self-renewal. We propose that Kismet with Trr establishes a chromatin state that limits EGFR proliferative signaling, preventing tumor-like stem cell overgrowths.

Highlights

Regulation of stem cell proliferation rates is critical in adult tissues, which need to maintain basal renewal and undergo damage-induced regenerative responses
We find that Trithoraxrelated complex (Trr) and Kismet co-localize in the genome and co-regulate the transcription of many genes, including Cbl, a negative regulator of Epidermal Growth Factor Receptor (EGFR)
Identification of kismet as an Essential Gene Controlling Stem Cell Homeostasis We screened for EMS-induced mutations affecting intestinal stem cell (ISC) activity and intestinal homeostasis (C.P., F.S., and A.B., unpublished data) and found one line (10D26) that showed an increase in the size of mutant clones generated in the midgut of adult flies (Figures 1B and 1C) and had a higher proportion of cells expressing Delta, an ISC marker (8.9 Delta+ cells; 44% of clone) when compared to the control (1.6 Delta+ cells, 20% of clone; Figure 1D)

Summary

Introduction

Regulation of stem cell proliferation rates is critical in adult tissues, which need to maintain basal renewal and undergo damage-induced regenerative responses. Of primary importance are signals that the ISCs receive to activate the Jak/ Stat and Epidermal Growth Factor Receptor (EGFR) pathways (Biteau and Jasper, 2011; Buchon et al, 2010, 2009; Jiang et al, 2011, 2009; Wang et al, 2014; Xu et al, 2011) Other pathways such as Insulin, Hippo, Jun Kinase, BMP, Wnt, and Hedgehog control ISC proliferation (Biteau et al, 2008; Cordero et al, 2012; Li et al, 2013, 2014; Lin et al, 2008; O’Brien et al, 2011; Ren et al, 2010; Shaw et al, 2010; Staley and Irvine, 2010; Tian and Jiang, 2014; Tian et al, 2015, 2017). Evidence suggests that there are mechanisms to limit ISC responsiveness, tuning down cell division when sufficient renewal has occurred (Guo et al, 2013; Hochmuth et al, 2011), though this process is not well understood

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