Stem cell proliferation is kept in check by the chromatin regulators Kismet/CHD7/CHD8 and Trr/MLL3/4

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. genome wild profiling of different chromatin factors in Drosophila intestinal stem cells by DamID and RNAseq on FACS sorted ISC expressing Kis RNAi Trr RNAi or white RNAi