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Activating transcription factors Atf3/4 drive early molecular events during neural stem cell differentiation and control neuron formation [RNA-seq]

ABSTRACT: The generation of new neurons from neural stem cells is tightly controlled by transcriptional programs. To induce cell fate switches that establish neuronal identities, differentiating neural precursor cells (NPCs) must undergo rapid and dynamic gene expression changes. However, the neuronal fate-determining molecular events that precede NPC differentiation are incompletely understood. Using high temporal resolution transcriptional profiling of adult hippocampal NPC differentiation, we here identified the activating transcription factors Atf3 and Atf4 as early switch regulators that drive NPC fate and control neuron formation. We found that Atf3/4 are rapidly upregulated in NPCs upon induction of differentiation and drive dynamic gene expression changes associated with neurogenesis. Pharmacological and genetic perturbation of Atf4 demonstrated its importance for neuron formation. Sustained overexpression of Atf3 hampered neurogenesis by repressing long non-coding RNA Miat. Our results demonstrate the critical role of an Atf3/Atf4-controlled transcriptional network in driving early molecular events during neurogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE253374 | GEO | 2024/01/18

REPOSITORIES: GEO

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Activating transcription factors Atf3/Atf4 drive early molecular events preceding neural stem cell differentiation and control neuron formation [Short]

Project description:The generation of new neurons from neural stem cells is tightly controlled by transcriptional programs. To induce cell fate switches that establish neuronal identities, differentiating neural precursor cells (NPCs) must undergo rapid and dynamic gene expression changes. However, the neuronal fate-determining molecular events that precede NPC differentiation are incompletely understood. Using high temporal resolution transcriptional profiling of adult hippocampal NPC differentiation, we here identified the activating transcription factors Atf3 and Atf4 as early switch regulators that drive NPC fate and control neuron formation. We found that Atf3/4 are rapidly upregulated in NPCs upon induction of differentiation and drive dynamic gene expression changes associated with neurogenesis. Pharmacological and genetic perturbation of Atf4 demonstrated its importance for neuron formation. Sustained overexpression of Atf3 hampered neurogenesis by repressing long non-coding RNA Miat. Our results demonstrate the critical role of an Atf3/Atf4-controlled transcriptional network in driving early molecular events during neurogenesis.

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Activating transcription factors Atf3/Atf4 drive early molecular events preceding neural stem cell differentiation and control neuron formation [Long]

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BET Bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cells

Project description:Neural stem cells (NSCs) and progenitor cells (NPCs) are increasingly appreciated to hold great promise for regenerative medicine to treat CNS injuries and neurodegenerative diseases. However, evidence for effective stimulation of neuronal production from endogenous or transplanted NPCs for cell replacement with small molecules remains limited. To identify novel chemical entities/targets for neurogenesis, we had established a NPC phenotypic screen assay and validated it using known small-molecule neurogenesis inducers. Through screening small molecule libraries with annotated targets, we identified BET bromodomain inhibition as a novel mechanism for enhancing neurogenesis. BET bromodomain proteins, Brd2, Brd3, and Brd4 were found to be downregulated in NPCs upon differentiation, while their levels remain unaltered in proliferating NPCs. Consistent with the pharmacological study using bromodomain selective inhibitor (+)-JQ-1, knockdown of each BET protein resulted in an increase in the number of neurons with simultaneous reduction in both astrocytes and oligodendrocytes. Gene expression profiling analysis demonstrated that BET bromodomain inhibition induced a broad but specific transcription program enhancing directed differentiation of NPCs into neurons while suppressing cell cycle progression and gliogenesis. Together, these results highlight a crucial role of BET proteins as promising epigenetic regulators in NPC development and suggest a therapeutic potential of BET inhibitors in treating CNS injury and neurodegenerative diseases. NPCs were treated with (+)-JQ-1 or inactive enantiomer (-)-JQ-1 at 0.2 Î¼M or 0.5 Î¼M for 12 and 24 hrs in differentiation medium. The experiments were carried out in 3 independent preparations of NPCs (triplicates)

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JMJD3 and UTX Determine Fidelity and Lineage Specification of Human Neural Progenitor Cells [ChIP-Seq]

Project description:Neurogenesis entails a highly orchestrated process from pluripotent to neural cell fates including progenitors (NPCs) and various neural subtypes. However, the precise epigenetic mechanisms underlying the fate decision remain poorly understood. Here, we deleted KDM6s (JMJD3 or/and UTX), the demethylases for H3K27me3, in human embryonic stem cells (hESCs) and show that their deletion does not impede NPC generation from hESCs. However, KDM6-deficient NPCs exhibit poor proliferation and fail to become neurons and glia. Mechanistically, KDM6 deficiency leads to H3K27me3 accumulation and blockade of DNA accessibility at loci essential for neurogenesis, thus hinder the fate transition from NPCs to neural subtypes. Our findings uncover an essential role of KDM6s in neurogenesis and highlight the contribution of individual epigenetic regulators in specifying lineage fidelity and fate decision during human development.

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JMJD3 and UTX Determine Fidelity and Lineage Specification of Human Neural Progenitor Cells [ChIP-seq]

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JMJD3 and UTX Determine Fidelity and Lineage Specification of Human Neural Progenitor Cells [ATAC-seq]

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JMJD3 and UTX Determine Fidelity and Lineage Specification of Human Neural Progenitor Cells [RNA-seq]

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