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Activator E2F family transcription factors are master regulators of the molecular signatures instructing the quiescent and activated adult neural stem cell state

ABSTRACT: The long-term maintenance of the adult neurogenic niche and neurogenesis is dependent on the proper regulation of entry and exit from quiescence. The dynamic transition from quiescence to activation is a complex process requiring not only precise cell cycle control, but also a co-ordinated phenotypic transition involving transcriptional and morphological changes. Presently, the mechanisms by which such a complex repertoire of factors interact and co-ordinate with the core cell cycle machinery to mediate these critical NSC fate transitions remains unknown. Here we show that the Rb/E2F axis functions as an on-off switch for NSC quiescence and activation, by linking the cell cycle machinery to pivotal regulators of NSC fate. Compound deletion of Rb family proteins results in massive activation and expansion of NSCs, and induces a global transcriptomic transition towards NSC activation followed by niche depletion. Deletion of their target activator E2Fs1/3 results in the failure of NSCs to become activated and the acquisition of a global transcriptome associated with intractable NSC quiescence and the cessation of adult neurogenesis. We further show that the Rb/E2F axis orchestrates these fate transitions through the direct regulation of factors essential to NSC function, including REST and ASCL1. This places the Rb/E2F axis as a master regulator of NSC fate, coordinating cell cycle control with NSC activation and quiescence fate transitions.

ORGANISM(S): Mus musculus

PROVIDER: GSE190764 | GEO | 2022/11/01

REPOSITORIES: GEO

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Rb family proteins are master regulators of the molecular signatures instructing the quiescent and activated adult neural stem cell state

Project description:The long-term maintenance of the adult neurogenic niche and neurogenesis is dependent on the proper regulation of entry and exit from quiescence. The dynamic transition from quiescence to activation is a complex process requiring not only precise cell cycle control, but also a co-ordinated phenotypic transition involving transcriptional and morphological changes. Presently, the mechanisms by which such a complex repertoire of factors interact and co-ordinate with the core cell cycle machinery to mediate these critical NSC fate transitions remains unknown. Here we show that the Rb/E2F axis functions as an on-off switch for NSC quiescence and activation, by linking the cell cycle machinery to pivotal regulators of NSC fate. Compound deletion of Rb family proteins results in massive activation and expansion of NSCs, and induces a global transcriptomic transition towards NSC activation followed by niche depletion. Deletion of their target activator E2Fs1/3 results in the failure of NSCs to become activated and the acquisition of a global transcriptome associated with intractable NSC quiescence and the cessation of adult neurogenesis. We further show that the Rb/E2F axis orchestrates these fate transitions through the direct regulation of factors essential to NSC function, including REST and ASCL1. This places the Rb/E2F axis as a master regulator of NSC fate, coordinating cell cycle control with NSC activation and quiescence fate transitions.

2022-11-01 | GSE190765 | GEO

MAZ induces MYB expression during the exit from quiescence via the E2F site in the MYB promoter

Project description:Most E2F-binding sites repress transcription through the recruitment of Retinoblasoma (RB) family members until the end of the G1 cell-cycle phase. Although the MYB promoter contains an E2F-binding site, its transcription is activated shortly after the exit from quiescence, before RB family members inactivation, by unknown mechanisms. We had previously uncovered a nuclear factor distinct from E2F, Myb-sp, whose DNA-binding site overlapped the E2F element and had hypothesized that this factor might overcome the transcriptional repression of MYB by E2F-RB family members. We have purified Myb-sp and discovered that Myc-associated zinc finger proteins (MAZ) are major components. We show that various MAZ isoforms are present in Myb-sp and activate transcription via the MYB-E2F element. Moreover, while forced RB or p130 expression repressed the activity of a luciferase reporter driven by the MYB-E2F element, co-expression of MAZ proteins not only reverted repression, but also activated transcription. Finally, we show that MAZ binds the MYB promoter in vivo, that its binding site is critical for MYB transactivation, and that MAZ knockdown inhibits MYB expression during the exit from quiescence. Together, these data indicate that MAZ is essential to bypass MYB promoter repression by RB family members and to induce MYB expression.

2017-10-04 | PXD006857 | Pride

Autofluorescence is a biomarker of neural stem cell activation state [Subventricular zone]

Project description:Neural stem cells (NSCs) in the adult brain are primarily quiescent but can activate and enter the cell cycle to produce newborn neurons. NSC quiescence can be regulated by disease, injury, and age, however our understanding of NSC quiescence is limited by technical limitations imposed by the bias of markers used to isolate each population of NSCs and the lack of live-cell labeling strategies. Fluorescence lifetime imaging (FLIM) of autofluorescent metabolic cofactors has previously been used in other cell types to study shifts in cell states driven by metabolic remodeling that change the optical properties of these endogenous fluorophores. Here we asked whether autofluorescence could be used to discriminate NSC activation state. We found that quiescent NSCs (qNSCs) and activated NSCs (aNSCs) each have unique autofluorescence intensity and fluorescence lifetime profiles. Additionally, qNSCs specifically display an enrichment of a specific autofluorescent signal localizing to lysosomes that is highly predictive of cell state. These signals can be used as a graded marker of NSC quiescence to predict cell behavior and track the dynamics of quiescence exit at single cell resolution in vitro and in vivo. Through coupling autofluorescence imaging with single-cell RNA sequencing in vitro and in vivo, we provide a high-resolution resource revealing transcriptional features linked to rapid NSC activation and deep quiescence. Taken together, we describe a single-cell resolution, non-destructive, live-cell, label-free strategy for measuring NSC activation state in vitro and in vivo and use this tool to expand our understanding of adult neurogenesis.

2024-02-09 | GSE223093 | GEO

Autofluorescence is a biomarker of neural stem cell activation state [Hippocampus]

2024-02-09 | GSE223092 | GEO

TRANSCRIPTIONAL ACTIVATION BY E2F4 INDEPENDENT OF THE RB FAMILY

Project description:E2F transcription factors are central regulators of cell cycle progression and cell fate decisions in mammalian cells. E2F4 is a transcriptional repressor implicated in cell cycle arrest and whose repressive activity depends on its interaction with members of the RB family. E2F4 often represents the predominant E2F activity in cells. Here we show that E2F4 is important for the proliferation and the survival of mouse embryonic stem cells. In these cells, E2F4 acts in part as a transcriptional activator that promotes the expression of cell cycle genes. Importantly, this role for E2F4 is completely independent of the RB family. Accordingly, an unbiased analysis of the E2F4 interactome shows that E2F4 functionally interacts with chromatin regulators associated with gene activation in RB family-mutant cells. Taken together, our findings uncover a non-canonical role for E2F4 that reveal novel insights into the biology of rapidly dividing cell types.

2019-04-26 | PXD008796 | Pride

Pandey2018-reversible transition between quiescence and proliferation

Project description:Cells switch between quiescence and proliferation states for maintaining tissue homeostasis and regeneration. At the restriction point (R-point), cells become irreversibly committed to the completion of the cell cycle independent of mitogen. The mechanism involving hyper-phosphorylation of retinoblastoma (Rb) and activation of transcription factor E2F is linked to the R-point passage. However, stress stimuli trigger exit from the cell cycle back to the mitogen-sensitive quiescent state after Rb hyper-phosphorylation but only until APC/CCdh1 inactivation. In this study, we developed a mathematical model to investigate the reversible transition between quiescence and proliferation in mammalian cells with respect to mitogen and stress signals. The model integrates the current mechanistic knowledge and accounts for the recent experimental observations with cells exiting quiescence and proliferating cells. We show that Cyclin E:Cdk2 couples Rb-E2F and APC/CCdh1 bistable switches and temporally segregates the R-point and the G1/S transition. A redox-dependent mutual antagonism between APC/CCdh1 and its inhibitor Emi1 makes the inactivation of APC/CCdh1 bistable. We show that the levels of Cdk inhibitor (CKI) and mitogen control the reversible transition between quiescence and proliferation. Further, we propose that shifting of the mitogen-induced transcriptional program to G2-phase in proliferating cells might result in an intermediate Cdk2 activity at the mitotic exit and in the immediate inactivation of APC/CCdh1. Our study builds a coherent framework and generates hypotheses that can be further explored by experiments.

2020-06-22 | BIOMD0000000954 | BioModels

LRIG1 is a gatekeeper to exit from quiescence in adult neural stem cells

Project description:Adult neural stem cells (NSCs) must tightly regulate quiescence and proliferation. Single cell analysis has suggested a continuum of cell states as NSCs exit quiescence. Here we capture and characterize in vitro primed quiescent NSCs and identify LRIG1 as an important regulator. We show that BMP-4 signaling induces a dormant non-cycling quiescent state (d-qNSCs), whereas combined BMP-4/FGF-2 signalling induces a distinct primed quiescent state poised for cell cycle re-entry. Primed quiescent NSCs (p-qNSCs) are defined by high levels of LRIG1 and CD9, as well as an interferon response signature, and can efficiently engraft into the adult subventricular zone (SVZ) niche. Genetic disruption of Lrig1 in vivo within the SVZ NSCs leads an enhanced proliferation. Mechanistically, LRIG1 primes quiescent NSCs for cell cycle re-entry and EGFR responsiveness by enabling EGFR protein levels to increase but limiting signaling activation. LRIG1 is therefore an important functional regulator of NSC exit from quiescence.

2021-03-18 | GSE168189 | GEO

Epigenetic maintenance of neural stem cell quiescence in the adult mouse hippocampus via Setd1a [RNA-Seq]

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

Epigenetic maintenance of neural stem cell quiescence in the adult mouse hippocampus via Setd1a [Cut & Run]

2024-03-31 | GSE250275 | GEO

SETD4 Cells Contribute to Brain Development and Maintain Adult Stem Cell Reservoir for Neurogenesis

Project description:Cellular quiescence facilitates maintenance of neural stem cells (NSCs) and their subsequent regenerative functions in response to brain injury and aging. However, the specification and maintenance of NSCs in quiescence from embryo to adulthood remains largely unclear. Here, using Set domain-containing protein 4 (SETD4), an epigenetic determinant of cellular quiescence, we mark a small but long-lived NSC population in deep quiescence in the subventricular zone of adult murine brain. Genetic lineage tracing shows that SETD4+ cells appear before neuroectoderm formation and contribute to brain development. In the adult, conditional knock-out of SETD4 resulted in quiescence exit of NSCs, generating newborn neurons in the olfactory bulb and contributing to damage repair. However, long period deletion of SETD4 lead to exhaustion of NSC reservoir or SETD4 overexpression caused quiescence entry of NSCs, leading to suppressed neurogenesis. This study reveals the existence of long-lived deep quiescent NSCs and their neurogenetic capacities beyond activation.

2022-08-25 | GSE200159 | GEO

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