Transcriptional Regulation of Intestinal Stem Cell Lineage in Drosophila

The question of how somatic stem cells respond to tissue needs is always intriguing, since aberrant somatic stem cell behaviors may lead to adult tissue degeneration or tumorigenesis. Here, this thesis focuses on the transcriptional regulation of a somatic stem cell lineage: the intestinal stem cell in Drosophila adult gut. The Drosophila adult gut is a dynamic organ. It is maintained by hundreds of somatic gut stem cell evenly distributed throughout the gut epithelium. These multi-potent somatic stem cells undergo self-renewal and differentiation to replenish two mature gut cell types: the absorptive enterocytes and secretory entero-endocrine cells. Through an RNAi screen targeting transcription factors required for stem cell-mediated acute gut regeneration, two novel transcription factors, the FoxA family Fork head (Fkh) and SoxE family sox100b (dSox9), were uncovered and functionally characterized in this thesis. During gut regeneration, transcription factor Fkh and dSox9 are required for stem cell proliferation. During gut homeostasis, Fkh maintains stemness and prevents progenitor from precocious differentiation; dSox9 controls lineage differentiation through Jak-Stat pathway. To further probe mechanisms underlying gut stem cell physiology, ChIP-Seq technique was applied to map chromatin binding sites of gut stem cell regulators (HA tagged) in stem/progenitor cells of dissected fly guts, including transcription factors (FoxA family/Fkh, SoxE family/dSox9, bHLH family/Da), niche pathway downstream factors (Jak-Stat pathway/Stat92E, BMP pathway/Mad, Notch pathway/Su(H), JNK pathway/Kay), and transcriptional regulators (Mediator/Med20, p300/Nej). A set of shared ChIP-Seq peak regions likely functions as enhancers to drive gene expression in gut stem/progenitor cells. This thesis leads to the speculation of a transcriptional network that maintains gut stem/progenitor cell normal physiology in adult Drosophila.