Epigenetic maintenance of neural stem cell quiescence in the adult mouse hippocampus via Setd1a
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PROVIDER: PRJNA1053284 | ENA |
REPOSITORIES: ENA
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Project description:Quiescence, a hallmark of adult neural stem cells (NSCs), is required for maintaining the NSC pool to support life-long continuous neurogenesis in the adult dentate gyrus (DG). Whether epigenetic mechanisms can maintain NSC quiescence over long term in the adult brain is not well-understood. Here we showed that adult mice with haploinsufficiency of Setd1a, a schizophrenia risk gene encoding a histone H3K4 methyltransferase, exhibited substantially enlarged DG with increased number of dentate granule cells. Deletion of Setd1a specifically in quiescent NSCs in the adult DG promoted their activation and neurogenesis, which was countered by inhibition of histone demethylase LSD1. Mechanistically, RNA sequencing and CUT & RUN analyses of cultured quiescent adult NSCs revealed Setd1a deletion-induced transcriptional changes and Setd1a targets, among which down-regulation of Bhlhe40 promoted quiescent NSC activation in the adult DG. Together, our study revealed a Setd1a-dependent epigenetic mechanism that sustains NSC quiescence in the adult DG.
2024-03-31 | GSE250276 | GEO
Project description:Quiescence, a hallmark of adult neural stem cells (NSCs), is required for maintaining the NSC pool to support life-long continuous neurogenesis in the adult dentate gyrus (DG). Whether epigenetic mechanisms can maintain NSC quiescence over long term in the adult brain is not well-understood. Here we showed that adult mice with haploinsufficiency of Setd1a, a schizophrenia risk gene encoding a histone H3K4 methyltransferase, exhibited substantially enlarged DG with increased number of dentate granule cells. Deletion of Setd1a specifically in quiescent NSCs in the adult DG promoted their activation and neurogenesis, which was countered by inhibition of histone demethylase LSD1. Mechanistically, RNA sequencing and CUT & RUN analyses of cultured quiescent adult NSCs revealed Setd1a deletion-induced transcriptional changes and Setd1a targets, among which down-regulation of Bhlhe40 promoted quiescent NSC activation in the adult DG. Together, our study revealed a Setd1a-dependent epigenetic mechanism that sustains NSC quiescence in the adult DG.
2024-03-31 | GSE250275 | GEO
Project description:Epigenetic maintenance of neural stem cell quiescence in the adult mouse hippocampus via Setd1a [Cut & Run]
| PRJNA1053285 | ENA
Project description:Epigenetic maintenance of neural stem cell quiescence in the adult mouse hippocampus via Setd1a [RNA-Seq]
| PRJNA1053286 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-03-31 | GSE250278 | GEO
Project description:Quiescence is essential for the long term maintenance of adult stem cells and tissue homeostasis. However, how stem cells maintain quiescence is still poorly understood. Here we show that stem cells in the dentate gyrus of the adult hippocampus actively transcribe the proactivation factor Ascl1 regardless of their activation state. We found that the inhibitor of DNA binding protein Id4 suppresses Ascl1 activity in neural stem cell cultures. Id4 sequesters Ascl1 heterodimerisation partner, promoting the degradation of Ascl1 protein and neural stem cell quiescence. Accordingly, elimination of Id4 from stem cells in the adult hippocampus results in abnormal accumulation of Ascl1 protein and premature stem cell activation. We also found that multiple signalling pathways converge on the regulation of Id4 to control the activity of hippocampal stem cells. Id4 therefore maintains quiescence of adult neural stem cells, in sharp contrast with its role of promoting the proliferation of embryonic neural progenitors.
2019-10-18 | GSE116997 | GEO
Project description:Adult hippocampal neurogenesis is important for certain forms of cognition and failing neurogenesis has been implicated in neuropsychiatric diseases. The neurogenic capacity of hippocampal neural stem/progenitor cells (NSPCs) depends on a balance between quiescent and proliferative states. However, how this balance is regulated remains poorly understood. Here we show that the rate of fatty acid oxidation (FAO) defines quiescence vs. proliferation in NSPCs. Quiescent NSPCs show high levels of carnitine palmitoyltransferase 1a (Cpt1a)-dependent FAO, which is downregulated in proliferating NSPCs. Pharmacological inhibition and conditional deletion of Cpt1a in vitro and in vivo leads to altered NSPC behavior, showing that Cpt1a-dependent FAO is required for stem cell maintenance and proper neurogenesis. Strikingly, experimental manipulation of malonyl-CoA, the metabolite that regulates levels of FAO, is sufficient to induce exit from quiescence and to enhance NSPC proliferation. Thus, the data presented here identify a shift in FAO metabolism that governs NSPC behavior and suggest an instructive role for fatty acid metabolism in regulating NSPC activity.
2019-11-15 | PXD005598 | Pride
Project description:Experience governs neurogenesis from radial-glial neural stem cells (RGLs) in the adult hippocampus to support memory. Transcription factors in RGLs integrate physiological signals to dictate quiescence-activation decisions and self-renewal divisions. Whereas asymmetric RGL self-renewal drives neurogenesis during favorable conditions, symmetric divisions prevent premature neurogenesis during unfavorable conditions while amplifying RGLs to anticipate neurogenic demands when conditions become favorable. Here, we show that the transcription factor Kruppel-like factor 9 (Klf9) is enriched in quiescent RGLs and inducible, bidirectional modulation of Klf9 biases RGL quiescence-activation decisions. Clonal lineage tracing and longitudinal intravital two-photon imaging of RGLs following cell-autonomous Klf9 deletion directly demonstrated increased symmetric self-renewal. In vivo translational profiling of RGLs identified a Klf9-dependent blueprint for genetic and metabolic programs instructing RGL quiescence and expansion. Thus, experience dependent regulation of Klf9 in RGLs may ensure self-preservation of neural stem cells while anticipating future demands for neurogenesis and astrogenesis to support hippocampal functions.
2022-01-06 | GSE164889 | GEO
Project description:Mapping physical interactions of SETD1A COMPOASS in HEK293T cells using endogenous immunoprecipitation followed by label-free quantitative proteomics. We found a novel protein interacts with SETD1A, which is RAD18 (DNA damage repair protein).
2019-06-13 | PXD012549 | Pride
Project description:SETD1A, a histone methyltransferase, is a key schizophrenia susceptibility gene. Mutant mice carrying a heterozygous loss-of-function mutation of the orthologous gene exhibit alterations in axonal branching and cortical synaptic dynamics, accompanied by specific deficits in working memory that recapitulates SCZ-related alterations. We show that Setd1a targets mostly enhancers and reveal a striking overlap between Setd1a and Mef2 chromatin targets. Setd1a targets are highly expressed in pyramidal neurons and enriched for genes with postnatally-biased expression involved in synaptic structure and function. Notably, evolutionary conserved Setd1a binding sites and target genes are strongly associated with neuropsychiatric genetic risk burden. Reinstating Setd1a expression in adulthood rescues working memory deficits. We identify LSD1 as a major demethylase counteracting the effects of Setd1a methyl transferase activity and show that LSD1 antagonism in adult Setd1a-deficient mice results in a full rescue of the behavioral abnormalities and axonal branching deficits. Our findings advance our understanding of how SETD1A mutations predispose to SCZ and point to therapeutic interventions.
2019-10-09 | GSE123652 | GEO