The Super Elongation Complex Drives Neural Stem Cell Fate Commitment

• Published in: Developmental cell 2017-03, Vol.40 (6), p.537-551.e6
• Main Authors: Liu, Kun, Shen, Dan, Shen, Jingwen, Gao, Shihong M., Li, Bo, Wong, Chouin, Feng, Weidong, Song, Yan
• Format: Article
• Language: English
• Subjects: Animals; Cell Dedifferentiation; cell fate commitment; cell fate decision; Cell Lineage; Cell Self Renewal; Drosophila melanogaster; Drosophila melanogaster - cytology; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - metabolism; Female; Genes, Insect; Male; neural stem cell; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; neuroblast; Notch signaling; progenitor dedifferentiation; Protein Binding; Protein Subunits - metabolism; Receptors, Notch - metabolism; SEC; Signal Transduction; super elongation complex; transcription elongation; Transcriptional Activation - genetics; tumorigenesis
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2017.02.022

Asymmetric stem cell division establishes an initial difference between a stem cell and its differentiating sibling, critical for maintaining homeostasis and preventing carcinogenesis. Yet the mechanisms that consolidate and lock in such initial fate bias remain obscure. Here, we use Drosophila neuroblasts to demonstrate that the super elongation complex (SEC) acts as an intrinsic amplifier to drive cell fate commitment. SEC is highly expressed in neuroblasts, where it promotes self-renewal by physically associating with Notch transcription activation complex and enhancing HES (hairy and E(spl)) transcription. HES in turn upregulates SEC activity, forming an unexpected self-reinforcing feedback loop with SEC. SEC inactivation leads to neuroblast loss, whereas its forced activation results in neural progenitor dedifferentiation and tumorigenesis. Our studies unveil an SEC-mediated intracellular amplifier mechanism in ensuring robustness and precision in stem cell fate commitment and provide mechanistic explanation for the highly frequent association of SEC overactivation with human cancers. [Display omitted] •Super elongation complex (SEC) subunits are highly expressed in neural stem cells•SEC forms a positive feedback loop with Notch signaling in promoting NSC self-renewal•Overactivation of SEC induces neural progenitor dedifferentiation and tumorigenesis•SEC acts as an intrinsic amplifier driving neural stem cell fate commitment Liu et al. implicate the super elongation complex (SEC), best known for transcription elongation checkpoint control, in driving Drosophila neural stem cell (NSC) fate commitment. SEC is highly expressed in NSCs, where it interacts directly with the Notch signaling pathway in a self-reinforcing feedback loop for timely stem cell fate lock-in.