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Dev Cell. 2019 May 20;49(4):556-573.e6. doi: 10.1016/j.devcel.2019.04.033.

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

Author information

1
Institut Curie, PSL Research University, CNRS UMR 3215, INSERM U934, Stem Cells and Tissue Homeostasis Group, Paris, France; Sorbonne Universités, UPMC Univ Paris 6, Paris, France. Electronic address: louis.gervais@curie.fr.
2
Institut Curie, PSL Research University, CNRS UMR 3215, INSERM U934, Stem Cells and Tissue Homeostasis Group, Paris, France; Sorbonne Universités, UPMC Univ Paris 6, Paris, France.
3
Institut Pasteur, Department of Developmental and Stem Cell Biology, Paris 75015, France; CNRS, URA2578, Rue du Dr Roux, Paris 75015, France.
4
The Gurdon Institute and Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 1QN, UK; Menzies Institute for Medical Research, University of Tasmania, 17 Liverpool Street Hobart, Tasmania, 7000, Australia.
5
The Gurdon Institute and Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 1QN, UK.
6
Institut Curie, PSL Research University, CNRS UMR 3215, INSERM U934, Stem Cells and Tissue Homeostasis Group, Paris, France; Sorbonne Universités, UPMC Univ Paris 6, Paris, France. Electronic address: allison.bardin@curie.fr.

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.

KEYWORDS:

Cbl; Drosophila midgut; EGFR; Epigenetic; Kismet/CHD7/CHD8; Proliferation control; Trr/MLL3/4; adult stem cells; chromatin regulators; tissue homeostasis

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