Stem Cell Proliferation Is Kept in Check by the Chromatin Regulators Kismet/CHD7/CHD8 and Trr/MLL3/4
| Autor: | Gervais, Louis, Van Den Beek, Marius, Josserand, Manon, Sallé, Jérémy, Stefanutti, Marine, Perdigoto, Carolina N, Skorski, Patricia, Mazouni, Khallil, Marshall, Owen J, Brand, Andrea H, Schweisguth, François, Bardin, Allison J |
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| Předmět: |
Cbl
tissue homeostasis EGFR adult stem cells Histones Kismet/CHD7/CHD8 Animals Drosophila Proteins Receptors Invertebrate Peptide Trr/MLL3/4 Cell Proliferation Homeodomain Proteins Stem Cells fungi DNA Helicases Epigenetic Cell Differentiation Histone-Lysine N-Methyltransferase Drosophila midgut Chromatin Assembly and Disassembly Chromatin 3. Good health ErbB Receptors Drosophila melanogaster chromatin regulators RNA Polymerase II Proliferation control Signal Transduction Transcription Factors |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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