Stage-specific Epigenetic Priming Amplifies Gene Activation During Lineage Commitment [CUT&Run]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE298002 | GEO | 2025/11/28
REPOSITORIES: GEO
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Project description:Neural progenitor cells exhibit developmental plasticity, as they are able to commit to different developmental trajectories in response to external stimuli. How these decisions are stabilized at the molecular level remains a highly active area of research. One way to stably integrate external stimuli into cell fate decisions is through epigenetic marks. H4K16ac represents a unique epigenetic mark, as it modulates chromatin compaction and is the only known active histone modification that is transmitted intergenerationally. The deposition of H4K16ac is mediated by the evolutionarily conserved MSL acetyltransferase complex (MSLc), via its catalytic subunit MOF, and mutations in its components have been linked to neurodevelopmental disorders. To dissect the role of the MSLc, we employed a multi-pronged strategy combining both chronic and acute depletion models. Deletion of the MSLc structural backbone Msl1 in vivo resulted in embryonic lethality by E10, and single-cell multi-omics analysis revealed a systemic disruption in lineage commitment within the neuroectoderm. To distinguish primary molecular functions from secondary developmental consequences, we complemented this with a rapid degradation system in vitro, coupled to directed differentiation into two distinct neural lineages. We found that the MSLc facilitates accessibility at regulatory elements in the early stages of lineage commitment during neurogenesis. We observe a significant decrease in enhancer-promoter contacts in a specific subset of neurodevelopmental genes. In the absence of MSLc this gene group fails to reach adequate gene expression levels upon differentiation, resulting in abnormal morphology. Intriguingly, MSLc loss later on during differentiation does not phenocopy this. Our work reveals MSLc-mediated gene priming as a crucial mechanism potentiating the transcriptional activation of neurodevelopmental gene programs. Our study describes a new mode of epigenetic regulation which cements initial cell fate decisions and provides molecular insights into MSLc-associated developmental disorders.
2025-11-28 | GSE298008 | GEO
Project description:Neural progenitor cells exhibit developmental plasticity, as they are able to commit to different developmental trajectories in response to external stimuli. How these decisions are stabilized at the molecular level remains a highly active area of research. One way to stably integrate external stimuli into cell fate decisions is through epigenetic marks. H4K16ac represents a unique epigenetic mark, as it modulates chromatin compaction and is the only known active histone modification that is transmitted intergenerationally. The deposition of H4K16ac is mediated by the evolutionarily conserved MSL acetyltransferase complex (MSLc), via its catalytic subunit MOF, and mutations in its components have been linked to neurodevelopmental disorders. To dissect the role of the MSLc, we employed a multi-pronged strategy combining both chronic and acute depletion models. Deletion of the MSLc structural backbone Msl1 in vivo resulted in embryonic lethality by E10, and single-cell multi-omics analysis revealed a systemic disruption in lineage commitment within the neuroectoderm. To distinguish primary molecular functions from secondary developmental consequences, we complemented this with a rapid degradation system in vitro, coupled to directed differentiation into two distinct neural lineages. We found that the MSLc facilitates accessibility at regulatory elements in the early stages of lineage commitment during neurogenesis. We observe a significant decrease in enhancer-promoter contacts in a specific subset of neurodevelopmental genes. In the absence of MSLc this gene group fails to reach adequate gene expression levels upon differentiation, resulting in abnormal morphology. Intriguingly, MSLc loss later on during differentiation does not phenocopy this. Our work reveals MSLc-mediated gene priming as a crucial mechanism potentiating the transcriptional activation of neurodevelopmental gene programs. Our study describes a new mode of epigenetic regulation which cements initial cell fate decisions and provides molecular insights into MSLc-associated developmental disorders.
2025-11-28 | GSE298005 | GEO
Project description:Neural progenitor cells exhibit developmental plasticity, as they are able to commit to different developmental trajectories in response to external stimuli. How these decisions are stabilized at the molecular level remains a highly active area of research. One way to stably integrate external stimuli into cell fate decisions is through epigenetic marks. H4K16ac represents a unique epigenetic mark, as it modulates chromatin compaction and is the only known active histone modification that is transmitted intergenerationally. The deposition of H4K16ac is mediated by the evolutionarily conserved MSL acetyltransferase complex (MSLc), via its catalytic subunit MOF, and mutations in its components have been linked to neurodevelopmental disorders. To dissect the role of the MSLc, we employed a multi-pronged strategy combining both chronic and acute depletion models. Deletion of the MSLc structural backbone Msl1 in vivo resulted in embryonic lethality by E10, and single-cell multi-omics analysis revealed a systemic disruption in lineage commitment within the neuroectoderm. To distinguish primary molecular functions from secondary developmental consequences, we complemented this with a rapid degradation system in vitro, coupled to directed differentiation into two distinct neural lineages. We found that the MSLc facilitates accessibility at regulatory elements in the early stages of lineage commitment during neurogenesis. We observe a significant decrease in enhancer-promoter contacts in a specific subset of neurodevelopmental genes. In the absence of MSLc this gene group fails to reach adequate gene expression levels upon differentiation, resulting in abnormal morphology. Intriguingly, MSLc loss later on during differentiation does not phenocopy this. Our work reveals MSLc-mediated gene priming as a crucial mechanism potentiating the transcriptional activation of neurodevelopmental gene programs. Our study describes a new mode of epigenetic regulation which cements initial cell fate decisions and provides molecular insights into MSLc-associated developmental disorders.
2025-11-28 | GSE298000 | GEO
Project description:Neural progenitor cells exhibit developmental plasticity, as they are able to commit to different developmental trajectories in response to external stimuli. How these decisions are stabilized at the molecular level remains a highly active area of research. One way to stably integrate external stimuli into cell fate decisions is through epigenetic marks. H4K16ac represents a unique epigenetic mark, as it modulates chromatin compaction and is the only known active histone modification that is transmitted intergenerationally. The deposition of H4K16ac is mediated by the evolutionarily conserved MSL acetyltransferase complex (MSLc), via its catalytic subunit MOF, and mutations in its components have been linked to neurodevelopmental disorders. To dissect the role of the MSLc, we employed a multi-pronged strategy combining both chronic and acute depletion models. Deletion of the MSLc structural backbone Msl1 in vivo resulted in embryonic lethality by E10, and single-cell multi-omics analysis revealed a systemic disruption in lineage commitment within the neuroectoderm. To distinguish primary molecular functions from secondary developmental consequences, we complemented this with a rapid degradation system in vitro, coupled to directed differentiation into two distinct neural lineages. We found that the MSLc facilitates accessibility at regulatory elements in the early stages of lineage commitment during neurogenesis. We observe a significant decrease in enhancer-promoter contacts in a specific subset of neurodevelopmental genes. In the absence of MSLc this gene group fails to reach adequate gene expression levels upon differentiation, resulting in abnormal morphology. Intriguingly, MSLc loss later on during differentiation does not phenocopy this. Our work reveals MSLc-mediated gene priming as a crucial mechanism potentiating the transcriptional activation of neurodevelopmental gene programs. Our study describes a new mode of epigenetic regulation which cements initial cell fate decisions and provides molecular insights into MSLc-associated developmental disorders.
2025-11-28 | GSE298001 | GEO
Project description:Neural progenitor cells exhibit developmental plasticity, as they are able to commit to different developmental trajectories in response to external stimuli. How these decisions are stabilized at the molecular level remains a highly active area of research. One way to stably integrate external stimuli into cell fate decisions is through epigenetic marks. H4K16ac represents a unique epigenetic mark, as it modulates chromatin compaction and is the only known active histone modification that is transmitted intergenerationally. The deposition of H4K16ac is mediated by the evolutionarily conserved MSL acetyltransferase complex (MSLc), via its catalytic subunit MOF, and mutations in its components have been linked to neurodevelopmental disorders. To dissect the role of the MSLc, we employed a multi-pronged strategy combining both chronic and acute depletion models. Deletion of the MSLc structural backbone Msl1 in vivo resulted in embryonic lethality by E10, and single-cell multi-omics analysis revealed a systemic disruption in lineage commitment within the neuroectoderm. To distinguish primary molecular functions from secondary developmental consequences, we complemented this with a rapid degradation system in vitro, coupled to directed differentiation into two distinct neural lineages. We found that the MSLc facilitates accessibility at regulatory elements in the early stages of lineage commitment during neurogenesis. We observe a significant decrease in enhancer-promoter contacts in a specific subset of neurodevelopmental genes. In the absence of MSLc this gene group fails to reach adequate gene expression levels upon differentiation, resulting in abnormal morphology. Intriguingly, MSLc loss later on during differentiation does not phenocopy this. Our work reveals MSLc-mediated gene priming as a crucial mechanism potentiating the transcriptional activation of neurodevelopmental gene programs. Our study describes a new mode of epigenetic regulation which cements initial cell fate decisions and provides molecular insights into MSLc-associated developmental disorders.
2025-11-28 | GSE298010 | GEO
Project description:Neural progenitor cells exhibit developmental plasticity, as they are able to commit to different developmental trajectories in response to external stimuli. How these decisions are stabilized at the molecular level remains a highly active area of research. One way to stably integrate external stimuli into cell fate decisions is through epigenetic marks. H4K16ac represents a unique epigenetic mark, as it modulates chromatin compaction and is the only known active histone modification that is transmitted intergenerationally. The deposition of H4K16ac is mediated by the evolutionarily conserved MSL acetyltransferase complex (MSLc), via its catalytic subunit MOF, and mutations in its components have been linked to neurodevelopmental disorders. To dissect the role of the MSLc, we employed a multi-pronged strategy combining both chronic and acute depletion models. Deletion of the MSLc structural backbone Msl1 in vivo resulted in embryonic lethality by E10, and single-cell multi-omics analysis revealed a systemic disruption in lineage commitment within the neuroectoderm. To distinguish primary molecular functions from secondary developmental consequences, we complemented this with a rapid degradation system in vitro, coupled to directed differentiation into two distinct neural lineages. We found that the MSLc facilitates accessibility at regulatory elements in the early stages of lineage commitment during neurogenesis. We observe a significant decrease in enhancer-promoter contacts in a specific subset of neurodevelopmental genes. In the absence of MSLc this gene group fails to reach adequate gene expression levels upon differentiation, resulting in abnormal morphology. Intriguingly, MSLc loss later on during differentiation does not phenocopy this. Our work reveals MSLc-mediated gene priming as a crucial mechanism potentiating the transcriptional activation of neurodevelopmental gene programs. Our study describes a new mode of epigenetic regulation which cements initial cell fate decisions and provides molecular insights into MSLc-associated developmental disorders.
2025-11-28 | GSE298006 | GEO
Project description:Genetic evidence indicates disrupted epigenetic regulation as a major risk factor for psychiatric disorders, but the molecular mechanisms that drive this association are undetermined. EHMT1 is an epigenetic repressor that is causal for Kleefstra Syndrome (KS), a neurodevelopmental disorder (NDD) leading to ID, and is associated with schizophrenia. Here, we show that reduced EHMT1 activity decreases NRSF/REST protein leading to abnormal neuronal gene expression and progression of neurodevelopment in human iPSC. We further show that EHMT1 regulates NRSF/REST indirectly via repression of miRNA leading to aberrant neuronal gene regulation and neurodevelopment timing. Expression of a NRSF/REST mRNA that lacks the miRNA-binding sites restores neuronal gene regulation to EHMT1 deficient cells. Importantly, the EHMT1-regulated miRNA gene set with elevated expression is enriched for NRSF/REST regulators with an association for ID and schizophrenia. This reveals a molecular interaction between H3K9 dimethylation and NSRF/REST contributing to the aetiology of psychiatric disorders.
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2011-10-30 | E-GEOD-32050 | biostudies-arrayexpress
Project description:DNA methylation dynamics influence brain function and are altered in neurological disorders. 5-hydroxymethylcytosine (5-hmC), a DNA base derived from 5-methylcytosine (5mC) accounts for ~40% of modified cytosine in brain, and has been implicated in DNA methylation-related plasticity. Here we map 5-hmC genome-wide across three ages in mouse hippocampus and cerebellum, allowing assessment of its stability and dynamic regulation during postnatal neurodevelopment through adulthood. We find developmentally programmed acquisition of 5-hmC in neuronal cells. Epigenomic localization of 5-hmC-regulated regions reveals stable and dynamically modified loci during neurodevelopment and aging. By profiling 5-hmC in human cerebellum we establish conserved genomic features of 5-hmC. Finally, we implicate 5-hmC in neurodevelopmental disease by finding that its levels are inversely correlated with methyl-CpG-binding protein 2 (Mecp2) dosage, a protein encoded by a gene in which mutations cause Rett Syndrome. These data point toward critical roles for 5-hmC-mediated epigenetic modification in neurodevelopment and diseases. Gene expression data derived from P7 and 6wk mouse cerebellum used for determining expression outcomes associated with dynamic alterations in 5-hydroxymethylcytosine
2011-10-29 | E-GEOD-32187 | biostudies-arrayexpress
Project description:CCSER1, a gene with limited prior knowledge in neurological conditions has emerged as a potential tumor suppressor and regulator of neurodevelopment. Our analysis reveals that CCSER1 downregulation correlates with down regulation of DNA repair and DNA replication pathways and up regulation of neurodevelopmental pathways, including calcium signaling and neuroactive ligand-receptor interaction, in CCSER1-deficient zebrafish. These findings suggest a potential role for CCSER1 in neurodevelopmental processes and its impact on adult behavior, as evidenced by altered alcohol preference in zebrafish models. Further investigation is needed to elucidate the precise molecular mechanisms underlying CCSER1 function and its contribution to human diseases, such as addiction and neurodevelopmental disorders.
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