A Poised Negative Feedback Circuit Balances Continual Self-Renewal with Rapid Restriction of Developmental Potential across Asymmetric Stem Cell Division.

[摘要] The identities of stem cells and their differentiated progeny are controlled by transcription factor networks that interact with chromatin modifying enzymes to package the genome into active and repressed domains. These transcription factor networks maintain stem cell identity across numerous rounds of self-renewing division through extensive auto- and feedforward-regulation, and by activating genes that are important for stem cell function. In addition, stem cell transcription factor networks directly regulate pro-differentiation genes, which are maintained in a poised chromatin state by the Polycomb group (PcG) and Trithorax group (TrxG) of chromatin modifying enzymes. How transcription factor networks maintain the poised chromatin state in stem cells, and coordinate the transition to an active chromatin state in their differentiating progeny remains unclear, and how this translates into the restriction of developmental potential is completely unknown. To elucidate mechanisms that regulate stem cell self-renewal and differentiation my thesis work focuses on a subset of neural stem cells in the fly larval brain, called type II neuroblasts, and their production of intermediate neural progenitors (INPs). Type II neuroblast identity is maintained by a core group of self-renewal transcriptional repressor proteins including Klumpfuss, Deadpan and E(spl)my, as well as lineage-specific transcriptional activators including Pointed-P1 and Buttonhead that endow type II neuroblasts with the competence to produce INPs. My work demonstrates that earmuff (erm) is specifically expressed in immature INPs, and functions as the master regulator of INP commitment, restricting their competence to respond to members of the self-renewal network by acting as a transcriptional repressor. In addition, we find the self-renewal transcriptional repressor network, lineage-specific transcriptional activators, and PcG and TrxG proteins converge to maintain the erm locus in a poised chromatin state in type II neuroblasts. Following asymmetric division, selective down-regulation of self-renewal transcriptional repressors in the immature INP allows rapid activation of erm expression. Erm then ensures stable commitment to a restricted INP identity by directly repressing components of the neuroblast transcription factor network. We propose the use of similar poised negative feedback circuits as a universal mechanism to balance continual self-renewal and rapid restriction of developmental potential across asymmetric stem cell division.

[发布机构] University of Michigan

[效力级别] Earmuff/dFezf1

[关键词] Stem cells;Earmuff/dFezf1;Poised enhancer;Self-renewal;Differentiation;Neurogenesis;Molecular;Cellular and Developmental Biology;Health Sciences;Cellular & Molecular Biology