The Chromatin Remodeling Factor Kismet/CHD7 Controls Intestinal Stem Cell Proliferation by limiting EGFR signaling

Specific gene expression programs allow the establishment and maintenance of stem cell identity and thereby control properties such as proliferation and differentiation. Major chromatin remodeling accompanies stem cell differentiation and is important for acquisition and maintenance of stable cell fates. The role of chromatin remodeling in controlling self-renewal properties of adult stem cells is less-well understood. We have performed an EMS mutagenesis screen and identified the chromatin remodeling factor kismet/CHD7 as a novel stem cell regulator essential to limit intestinal stem cell (ISC) number and proliferation in Drosophila. Whole genome profiling of Kismet in the ISC by targeted DamID revealed that Kismet binds directly to several genes involved in ISC self-renewal including the repressor of EGFR signaling, Capicua. Stem cell clones mutant for kismet exhibit aberrant activation of the EGFR pathway. The knock down of EGFR components or reexpression of Capicua rescue not only stem cell proliferation defects, but also stem cell aberrant accumulation. We further find that the Trithorax-related complex acts similarly to control ISC proliferation and colocalizes with Kismet on salivary gland polytene chromosomes, suggesting a close collaboration of these chromatin remodeling enzymes. We propose that Kismet along with the Trr-Complex establish a chromatin state required to limits proliferative signaling thereby preventing the development of tumor-like stem cell overgrowths.