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Chromodomain protein CDYL confers forebrain identity to human cortical organoids by inhibiting neuronatin [ChIP-seq]

ABSTRACT: Fate determination of neural stem cells is crucial for cerebral cortex development and is closely linked to neurodevelopmental disorders when gene expression networks are disrupted. The transcriptional corepressor chromodomain Y-like (CDYL) is widely expressed across diverse cell populations within the human embryonic cortex, though its precise role in this complex developmental process remains unclear. Here, we show that CDYL is critical for human cortical neurogenesis. CDYL deficiency leads to a substantial increase in gamma-aminobutyric acid (GABA)-ergic neurons in human cortical organoids, instead of the expected generation of typical cortical neurons. Subsequently, neuronatin (NNAT) is identified as a significant target of CDYL in this process, and its abnormal expression obviously influences the proliferation and fate commitment of cortical neural stem cells (NSCs) within human cortical organoids. Cross-species comparisons of CDYL targets unravel a distinct developmental trajectory between human cortical organoids and mouse cortex at an analogous stage. Collectively, our data provide insight into the evolutionary roles of CDYL in human cortex development, emphasizing the critical function of CDYL in maintaining the fate of human cortical NSCs.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE276321 | GEO | 2024/09/18

REPOSITORIES: GEO

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Chromodomain protein CDYL confers forebrain identity to human cortical organoids by inhibiting neuronatin [RNA-seq]

Project description:Epigenetic regulation is essential for the normal development of human cerebral cortex, and its disruptions would lead to diverse neurodevelopmental disorders. The epigenetic co-repressor CDYL exhibits widespread expression across various cell clusters within the human embryonic cortex, yet its roles in this intricate process have remained elusive. Here, we show that CDYL is critical for cortical neurogenesis, and CDYL deficiency led to an augmentation in the generation of GABAergic neurons instead of cortical progenitors and neurons in the cortical organoid model. Combining analysis of bulk RNA-seq and ChIP seq, we identified NNAT as a significant CDYL target by H3K27me3 modification, crucial for the fate determination of neural stem cells within human cortical organoids, distinctly diverging from the murine cortex at a similar developmental stage. Collectively, our study sheds light on the critical function of CDYL in the maintenance of cortical neural stem cell fate commitment during human corticogenesis through the inhibition of NNAT expression.

2024-09-18 | GSE276320 | GEO

Co-repressor CDYL confers forebrain identity to human cortical organoids by negatively regulating NNAT [RNA-Seq]

2023-11-13 | GSE247084 | GEO

Co-repressor CDYL confers forebrain identity to human cortical organoids by negatively regulating NNAT [ChIP-Seq]

2023-11-13 | GSE247086 | GEO

Transcriptomic analysis of the hypothalamic paraventricular and the arcuate nucleus of NNAT null mice

Project description:Neuronatin (Nnat) has previously been reported to be part of a network of imprinted genes. Disruption of neuronatin results in an unusual phenotype of a bimodal body weight.In order to understand at the molecular level how the Nnat deficiency could contribute to the hypervariable phenotypes seen, we performed RNA sequencing from laser-capture micro dissected paraventricular nucleus (PVN) and arcuate nucleus (ARC) and compared the transcriptome between Nnat+/-p mice and their Nnat+/+ littermates in different feeding conditions. We performed an analysis of three subgroups: Nnat+/+ (all non-obese), Nnat+/-p non-obese, and Nnat+/-p obese mice and combined two approaches to identify differences in hypothalamic gene expression between subgroups

2021-09-03 | GSE171155 | GEO

CDYL ChIP-Seq in mouse hippocampus

Project description:Here we report that the epigenetic factor Chromodomain Y-like (CDYL) protein is a critical regulator for the initiation and maintenance of activity-dependent intrinsic neuroplasticity. Genome-wide ChIP-sequencing analysis revealed that CDYL regulates multiple neuronal functional pathways including voltage-gated ion channels in mouse brains. We showed that CDYL binds to a regulatory element in the intron region of SCN8A and mainly recruits H3K27me3 activity for transcriptional repression of the gene. Injection of lentivirally-delivered CDYL shRNA to rat hippocampal neurons resulted in augmented Nav1.6-mediated sodium currents, lower neuronal threshold and increased seizure susceptibility, whereas transgenic mice over-expressing CDYL had higher neuronal threshold and were less prone to epileptogenesis. Finally, examination of human brain tissues revealed decreased expression of CDYL and increased expression of SCN8A in the temporal lobe epilepsy group. Together, our findings indicate CDYL is a critical player for experience-dependent gene regulation in controlling intrinsic excitability, which potentially contributes to learning and memory and CNS disorders involving change in activity such as epilepsy.

2017-06-25 | GSE96721 | GEO

Biological significance of CDYL in endometrial receptivity

Project description:Impaired endometrial receptivity is one of the major causes of recurrent implantation failure (RIF), and the underlying molecular mechanism has not been fully elucidated. We demonstrated that Chromodomain Y like (CDYL) was highly expressed in the endometrium at mid-secretory phase during the normal menstrual cycles. However, the expression of CDYL was down-regulated in the endometrial tissues obtained from women with RIF, consistently with the protein level of LIF, which is the marker of endometrial receptivity. Knockdown of CDYL significantly decreased the cell migration of human endometrial Ishikawa cells and primary endometrial cells. Genomic analyses revealed that CDYL gene silencing resulted in decreased expression of many genes associated with cytoskeleton and migration regulation.

2020-09-28 | GSE141239 | GEO

Nuclear condensation of CDYL links histone crotonylation and cystogenesis in autosomal dominant polycystic kidney disease [ChIP-Seq]

Project description:Background:molecular mechanisms coupling cellular metabolisms with the epigenome in cystic cells remains largely unknown Methods:To investigate the molecular mechanisms underlying the suppression of cyst growth by CDYL overexpression, we generated an engineered ADPKD cell line by stably expressing CDYL with TY1 tag in WT 9-12 human ADPKD cells (CDYL OE). We profiled genome-wide distribution of CDYL through chromatin immunoprecipitation coupled with sequencing (ChIP-seq) analysis in both parental WT 9-12 cells (control) and CDYL OE cells. Genetic overexpression of CDYL reduces histone Kcr. We examined histone Kcr on CDYL-target genes by performing ChIP-seq analyses using antibody recognizing PanKcr and H3K18cr in control and CDYL OE cells. Results: Using integrative cistromic and transcriptomic analyses, CDYL-regulated cyst-associated genes are identified, whose downregulation depends on CDYL-mediated suppression of histone Kcr. Conclusions: Thus, through establishing a metabolic niche via nuclear condensation, CDYL connects metabolic changes to transcriptional response via histone Kcr in ADPKD.

2022-05-24 | GSE183511 | GEO

Nuclear condensation of CDYL links histone crotonylation and cystogenesis in autosomal dominant polycystic kidney disease [RNA-Seq]

2022-05-24 | GSE183510 | GEO

ChIP-seq data of CDYL in mouse dorsal root ganglia

Project description:We report that the epigenetic factor CDYL is crucial for pain processing. CDYL downstreams in mouse dorsal root ganglia (DRG) are mostly associated with neurological functions, including chemical synaptic transmission, regulation of membrane potential and ion transport. CDYL facilitates H3K27me3 deposition at the Kcnb1 intron region thus silencing Kv2.1 transcription. Loss function of CDYL enhances total Kv and Kv2.1 current density in DRG and knockdown of Kv2.1 reverses the pain-related phenotypes of Cdyl deficiency mice.

2022-02-08 | GSE190751 | GEO

Enhanced cortical neural stem cell identity through SMAD/WNT inhibition in human cerebral organoids facilitates emergence of outer radial glial cells

Project description:Cerebral organoids exhibit broad regional heterogeneity accompanied by limited cortical cellular diversity despite the tremendous upsurge in derivation methods, suggesting inadequate patterning of early neural stem cells (NSCs). Here we show that a short and early dual-SMAD/WNT inhibition course is necessary and sufficient for establishing robust and lasting cortical organoid NSC identity, efficiently suppressing of non-cortical NSC fates, while other widely used methods are inconsistent in their cortical NSC specification capacity. Accordingly, this method selectively enriches for outer radial glia (oRG) NSCs, which cytoarchitecturally demarcate well-defined outer sub-ventricular (oSVZ)-like regions propagating from superiorly radially organized, apical cortical rosette NSCs. Finally, this method culminates in the emergence of molecularly distinct deep and upper cortical layer neurons, and reliably uncovers cortex-specific microcephaly defects. Thus, a short SMAD/WNT inhibition is critical for establishing a rich cortical cell repertoire that enables mirroring fundamental molecular and cytoarchitectural features of cortical development and meaningful disease modeling.

| EGAS00001006063 | EGA

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