Stem Cell Proliferation Is Kept in Check by the Chromatin Regulators Kismet/CHD7/CHD8 and Trr/MLL3/4.
van den Beek, Marius
Perdigoto, Carolina N
Marshall, Owen J
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Gervais, L., van den Beek, M., Josserand, M., Sallé, J., Stefanutti, M., Perdigoto, C. N., Skorski, P., et al. (2019). Stem Cell Proliferation Is Kept in Check by the Chromatin Regulators Kismet/CHD7/CHD8 and Trr/MLL3/4.. Developmental cell, 49 (4), 556-573.e6. https://doi.org/10.1016/j.devcel.2019.04.033
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 cells (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 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 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.
Chromatin, Stem Cells, Animals, Drosophila melanogaster, DNA Helicases, Histone-Lysine N-Methyltransferase, RNA Polymerase II, Homeodomain Proteins, Drosophila Proteins, Receptors, Invertebrate Peptide, Histones, Transcription Factors, Signal Transduction, Cell Differentiation, Cell Proliferation, Chromatin Assembly and Disassembly, ErbB Receptors
WELLCOME TRUST (103792/Z/14/Z)
Royal Society (RP150061)
Wellcome Trust (092096/Z/10/Z)
Cancer Research UK (A14492)
External DOI: https://doi.org/10.1016/j.devcel.2019.04.033
This record's URL: https://www.repository.cam.ac.uk/handle/1810/292052
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/