BCL6 controls neurogenesis through Sirt1-dependent epigenetic repression of selective Notch targets

Abstract

During neurogenesis, neural stem/progenitor cells (NPCs) undergo an irreversible fate transition to become neurons. The Notch pathway is important for this process, and repression of Notch-dependent Hes genes is essential for triggering differentiation. However, Notch signaling often remains active throughout neuronal differentiation, implying a change in the transcriptional responsiveness to Notch during the neurogenic transition. We identified Bcl6, an oncogene, as encoding a proneurogenic factor that is required for proper neurogenesis of the mouse cerebral cortex. BCL6 promoted the neurogenic conversion by switching the composition of Notch-dependent transcriptional complexes at the Hes5 promoter. BCL6 triggered exclusion of the co-activator Mastermind-like 1 and recruitment of the NAD(+)-dependent deacetylase Sirt1, which was required for BCL6-dependent neurogenesis. The resulting epigenetic silencing of Hes5 led to neuronal differentiation despite active Notch signaling. Our findings suggest a role for BCL6 in neurogenesis and uncover Notch-BCL6-Sirt1 interactions that may affect other aspects of physiology and disease.

SIRT1 suppresses self-renewal of adult hippocampal neural stem cells

“…9A,B), suggesting a conserved mechanism of SIRT1 regulation of Notch signaling between endothelial cells and aNSCs. Furthermore, SIRT1 could also serve as a component of the histone-modifying co-repressor complex, which represses Notch target gene expression in mouse embryonic fibroblasts or mouse embryonic progenitor cells (Mulligan et al, 2011;Tiberi et al, 2012). Although we failed to detect direct epigenetic repression by ChIP-Seq, transcriptional regulation of Notch target genes by SIRT1 in aNSCs remains a possibility to be further examined.…”

Regenerative Neurogenesis After Ischemic Stroke Promoted by Nicotinamide Phosphoribosyltransferase–Nicotinamide Adenine Dinucleotide Cascade

“…25 Most of biological functions of Nampt-NAD cascade were mediated by sirtuins, including SIRT1 for neuroprotection against acute cerebral ischemia, 11 SIRT3/4 for protecting against cell death, 9 and SIRT6 for synthesis of tumor necrosis factor. 8 SIRT1 to 7 were knocked down with specific siRNA by nucleofection in NSCs ( Figure IX in the online-only Data Supplement).…”

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

“…Bcl6 is detected at low levels in NSCs and high levels in INPs, where it reduces occupancy of the Mam-1 co-activator protein at the Hes5 locus, increases occupancy of the Sirt-1 deacetylase, leading to silencing of the Hes5 gene. 56 The authors conclude that epigenetic silencing of the Hes5 locus blocks productive Notch signaling in INPs leading to neuronal differentiation. It will be interesting to compare this mechanism to that of Eyeless blocking Notch signaling in Drosophila old INPs (see above); perhaps in both cases loss of competence to respond to Notch will be due to epigenetic silencing of specific Notch target genes.…”

“…In contrast, NSC progeny called intermediate neural progenitors (INPs) are exposed to Notch ligands but fail to express Notch target genes including a CSL reporter construct or Hes5, and thus initiate neuronal differentiation. 55,56 What limits INP competence to respond to Notch/CSL signaling? Recent work has shown that the Bcl6 oncogene is required to blunt Notch signaling in INPs.…”