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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Gervais, Louis 
van den Beek, Marius 
Josserand, Manon 
Sallé, Jérémy 
Stefanutti, Marine 

Abstract

Chromatin 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.

Description

Keywords

Cbl, Drosophila midgut, EGFR, Epigenetic, Kismet/CHD7/CHD8, Proliferation control, Trr/MLL3/4, adult stem cells, chromatin regulators, tissue homeostasis, Animals, Cell Differentiation, Cell Proliferation, Chromatin, Chromatin Assembly and Disassembly, DNA Helicases, Drosophila Proteins, Drosophila melanogaster, ErbB Receptors, Histone-Lysine N-Methyltransferase, Histones, Homeodomain Proteins, RNA Polymerase II, Receptors, Invertebrate Peptide, Signal Transduction, Stem Cells, Transcription Factors

Journal Title

Dev Cell

Conference Name

Journal ISSN

1534-5807
1878-1551

Volume Title

49

Publisher

Elsevier BV
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/L00786X/1)
Wellcome Trust (103792/Z/14/Z)
Royal Society (RP150061)
Wellcome Trust (092096/Z/10/Z)
Cancer Research Uk (None)