An Hdac1/Rpd3-Poised Circuit Balances Continual Self-Renewal and Rapid Restriction of Developmental Potential during Asymmetric Stem Cell Division

Abstract

SummaryHow the developmental potential of differentiating stem cell progeny becomes rapidly and stably restricted following asymmetric stem cell division is unclear. In the fly larval brain, earmuff (erm) uniquely functions to restrict the developmental potential of intermediate neural progenitors (INPs) generated by asymmetrically dividing neural stem cells (neuroblasts). Here we demonstrate that the histone deacetylase Hdac1/Rpd3 functions together with self-renewal transcriptional repressors to maintain the erm immature INP enhancer in an inactive but poised state in neuroblasts. Within two-hours of immature INP birth, down-regulation of repressor activities alleviates Rpd3-mediated repression on the erm enhancer, enabling acetylation of multiple histone proteins and activating Erm expression. Erm restricts the developmental potential in immature INPs by repressing genes encoding neuroblast transcriptional activators. We propose that poising the fast-activating enhancers of master regulators of differentiation through continual histone

bHLH-O proteins balance the self-renewal and differentiation of Drosophila neural stem cells by regulating Earmuff expression

“…However, PntP1 may not be the only target of Erm in imINPs. As shown in a recent study, in addition to PntP1, Erm also directly inhibits the expression of Grh-O in imINPs (Janssens et al, 2017). Therefore, Erm likely promotes the maturation of INPs by regulating the expression/function of multiple target genes.…”

“…Recently studies have shown that Erm could inhibit the expression of PntP1 and antagonize the function of PntP1 (Janssens et al, 2017; Li et al, 2016). Therefore, we wondered whether Erm promotes INP maturation by similarly inhibiting the expression and/or function of PntP1 in imINPs, in which both PntP1 and Erm are expressed (Janssens et al, 2014; Zhu et al, 2011), and whether the de-repression of PntP1’s expression and/or function in imINPs contribute to the dedifferentiation of imINPs resulting from the loss of Erm and misexpression of Dpn or E(spl) proteins.…”

“…Therefore, Dpn and Notch signaling may not be completely functionally redundant in suppressing the ectopic Erm expression or maintaining type II NBs, and their functions might be dependent on developmental stages. Furthermore, a recent study reported that Klu could also bind to the R9D11 enhancer to repress the expression of Erm (Janssens et al, 2017). Thus, type II NBs likely utilize multiple mechanisms to ensure that erm will not be prematurely activated.…”

Continual inactivation of genes involved in stem cell functional identity stabilizes progenitor commitment

“…The Sp8 family transcription factor Buttonhead (Btd) and the ETS-1 transcription factor PointedP1 (PntP1) are specifically expressed in type II neuroblasts (Komori et al, 2014a;Xie et al, 2014;Zhu et al, 2011). Btd Notch signaling maintains type II neuroblasts in an undifferentiated state partly by poising transcription of the master regulator of differentiation earmuff (erm) (Janssens et al, 2017). During asymmetric neuroblast division, the TRIM-NHL protein Brain tumor (Brat) segregates into the newly born immature INP, and targets transcripts encoded by downstream effector genes of Notch for RNA decay Betschinger et al, 2006;Komori et al, 2018;Lee et al, 2006;Xiao et al, 2012).…”

Opportunities lost and gained: Changes in progenitor competence during nervous system development

“…They showed that the erm enhancer is maintained in a poised state within type II neuroblasts by the Hdac1/Rpd3 histone deacetylase complex. 35 This prevents the activation of differentiation programs in parental neuroblasts, but enables the rapid activation of erm in their immature INP progeny, and their subsequently limited proliferative potential. In addition, Rpd3 deacetylation activity was required for type II neuroblast responsiveness to the self-renewal factors Deadpan, Klumpfuss and E(spl)m-gamma, indicating that these transcription factors utilize a specific epigenetic landscape in type II NBs to promote selfrenewal.…”