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Role of MicroRNA155 in Hippocampal Neurogenesis and GABAergic Signaling in Alzheimer’s Disease [MIR155 Knockout RNA Sequencing Data]

ABSTRACT: MicroRNA (miRNA) dysfunctions are implicated in neurodegenerative disorders, with microglial miR155 dysregulation extensively linked to neuroinflammation in Alzheimer's disease (AD). However, its role in other neural cell types remains unclear. Expanding on previous studies showing miR155 upregulation in hippocampal neurons of both AD model mice and AD patients, we found that in human induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs), MIR155 regulates NSC proliferation, with MIR155 deletion increasing NSC numbers and overexpression downregulating NSC markers. In cortical neurons, MIR155 deletion is associated with increased neuronal outgrowth and GABAergic interneuron generation. In cortical organoids, MIR155 deletion promotes ventral patterning and increases GABAergic interneuron formation. Deleting miR155 in an AD mouse model induced the expansion of hippocampal NSCs in the sub-granular zone (SGZ) and the hilus, and promoted an increase in the number of hippocampal GABAergic interneurons, highlighting the novel role of miR155 in adult hippocampal neurogenesis and GABAergic interneuron signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277199 | GEO | 2026/08/12

REPOSITORIES: GEO

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Project description:A cardinal property of neural stem cells (NSCs) is their ability to adopt multiple fates upon differentiation. The epigenome is widely seen as a read-out of cellular potential and a manifestation of this can be seen in embryonic stem cells (ESCs), where promoters of many lineage-specific regulators are marked by a bivalent epigenetic signature comprising trimethylation of both lysine 4 and lysine 27 of histone H3 (H3K4me3 and H3K27me3, respectively). Bivalency has subsequently emerged as a powerful epigenetic indicator of stem cell potential. Here, we have interrogated the epigenome during differentiation of ESC-derived NSCs to immature GABAergic interneurons. We show that developmental transitions are accompanied by loss of bivalency at many promoters in line with their increasing developmental restriction from pluripotent ESC through multipotent NSC to committed GABAergic interneuron. At the NSC stage, the promoters of genes encoding many transcriptional regulators required for differentiation of multiple neuronal subtypes and neural crest appear to be bivalent, consistent with the broad developmental potential of NSCs. Upon differentiation to GABAergic neurons, all non-GABAergic promoters resolve to H3K27me3 monovalency, whereas GABAergic promoters resolve to H3K4me3 monovalency or retain bivalency. Importantly, many of these epigenetic changes occur prior to any corresponding changes in gene expression. Intriguingly, another group of gene promoters gain bivalency as NSCs differentiate toward neurons, the majority of which are associated with functions connected with maturation and establishment and maintenance of connectivity. These data show that bivalency provides a dynamic epigenetic signature of developmental potential in both NSCs and in early neurons. Illumina Expresson BeadChip arrays (MouseRef-8v2.0) were used to assess gene expression changes in neural stem cells (n=5; derived from mouse embryonic stem cells) and their differentiated neuronal progeny (n=3; FACS-purified based on Tau-RedStar expression).

Project description:A cardinal property of neural stem cells (NSCs) is their ability to adopt multiple fates upon differentiation. The epigenome is widely seen as a read-out of cellular potential and a manifestation of this can be seen in embryonic stem cells (ESCs), where promoters of many lineage-specific regulators are marked by a bivalent epigenetic signature comprising trimethylation of both lysine 4 and lysine 27 of histone H3 (H3K4me3 and H3K27me3, respectively). Bivalency has subsequently emerged as a powerful epigenetic indicator of stem cell potential. Here, we have interrogated the epigenome during differentiation of ESC-derived NSCs to immature GABAergic interneurons. We show that developmental transitions are accompanied by loss of bivalency at many promoters in line with their increasing developmental restriction from pluripotent ESC through multipotent NSC to committed GABAergic interneuron. At the NSC stage, the promoters of genes encoding many transcriptional regulators required for differentiation of multiple neuronal subtypes and neural crest appear to be bivalent, consistent with the broad developmental potential of NSCs. Upon differentiation to GABAergic neurons, all non-GABAergic promoters resolve to H3K27me3 monovalency, whereas GABAergic promoters resolve to H3K4me3 monovalency or retain bivalency. Importantly, many of these epigenetic changes occur prior to any corresponding changes in gene expression. Intriguingly, another group of gene promoters gain bivalency as NSCs differentiate toward neurons, the majority of which are associated with functions connected with maturation and establishment and maintenance of connectivity. These data show that bivalency provides a dynamic epigenetic signature of developmental potential in both NSCs and in early neurons. Neural stem cells derived from mouse embryonic stem cells were differentiated into neurons and FACS purified based on RedStar fluorescence driven by the Tau promoter. Chromatin was prepared from NSCs and neurons (n=1), sonicated to roughly 300bp and immunoprecipitated with antibodies against H3K4me3, H3K27me3, total Histone H3 and total IgG, alongside a 5% input sample. K4/K27 and corresponding input samples were analysed by ChIPSeq

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Role of MicroRNA155 in Hippocampal Neurogenesis and GABAergic Signaling in Alzheimer’s Disease [MIR155 Knockout RNA Sequencing Data]

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