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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE183511 | GEO | 2022/05/24

REPOSITORIES: GEO

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Nuclear condensation of CDYL links histone crotonylation and cystogenesis in autosomal dominant polycystic kidney disease [RNA-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 | GSE183510 | GEO

The Role of CDYL-Regulated Crotonylation of RPA1 in Homologous Recombination-Mediated DNA Repair

Project description:Lysine crotonylation (Kcr) is a recently-identified protein short-chain acylation. We have previously reported that chromodomain Y-like transcription corepressor CDYL acts as a crotonyl-CoA hydratase and negatively regulates histone Kcr. However, the global crotonylome of CDYL-regulated Kcr on non-histone substrates remains unclear. Using proteome-wide quantitative Kcr analysis, we identified 14,311 Kcr sites across 3,734 proteins in HeLa cells, providing by far the largest crotonylome data set from a single study. Upon depletion of CDYL, 1,141 Kcr sites from 759 proteins were increased by more than 1.5 fold, and 933 Kcr sites from 528 proteins were decreased by more than 0.67 fold. Upregulated crotonylome alterations upon CDYL depletion include components from diverse cellular pathways such as RNA splicing, DNA replication, and amino acid metabolism. Specifically, CDYL regulates K88 and K379 of crotonylation on RPA1, which affects its binding to other DNA repair factors including BLM, DNA2L, RAD50 and WRN. We showed evidence that CDYL-mediated RPA1 crotonylation is critical for the homologous recombination (HR) repair of camptothecin (CPT)-induced DNA damage. Together, our results provide a broad lysine crotonylome in response to CDYL and shed new light on the role of RPA1 Kcr in DNA repair, implicating functional importance of Kcr on non-histone substrates in diverse cellular processes.

2020-04-02 | PXD013616 | Pride

Nuclear condensation of CDYL links histone crotonylation and cystogenesis in autosomal dominant polycystic kidney disease

Project description:We identify the Kcr sites on histones that are targeted by CDYL in ADPKD cells (WT9-12 cells). We chose to knock out CDYL in WT 9-12 cells (CDYL KO) through CRISPR/Cas9-mediated gene editing to increase the overall levels of histone Kcr. We quantified Kcr modifications on different histone residues in CDYL KO versus parental WT 9-12 cells (control) using high-resolution liquid chromatography tandem mass spectrometry (LC-MS/MS)-based proteomics analysis

2022-01-17 | PXD031029 |

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

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.

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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.

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Alteration of gene expression in E11.5 XY Cdyl deficient gonadal somatic cells

Project description:Cdyl deficient mice exhibited partial sex reversal. To determine this cause, RNA-seq was used to identify genes with altered expression in Cdyl deficient gonads.

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

Project description: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.

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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.

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

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