H3K4me3 profiling of Kdm1a/Kdm5c double-inducible forebrain-specific knockouts
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PROVIDER: PRJNA1255570 | ENA |
REPOSITORIES: ENA
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Project description:Loss or reduced expression of lysine demethylases (KDMs) is linked to neurodevelopmental disorders and intellectual disability. Given the phenotypic similarities between KDM1A and KDM5C deficient mice, and the convergence of both enzymes in maintaining a repressive state via H3K4 demethylation, we examined their functional interaction using double-inducible, forebrain-specific knockouts (dKDM-ifKOs). These mice showed transcriptional and epigenetic dysregulation beyond the additive effects of individual knockouts, including stronger ectopic expression of non-neuronal genes in hippocampal neurons. Thousands of de novo H3K4me3-enriched regions emerged, indicating synergistic disruption of chromatin regulation. In line with these molecular changes, dKDM-ifKOs displayed more severe behavioral impairments than the single ifKOs, along with altered hippocampal expression of ion channels and increased excitability of CA1 pyramidal neurons. These findings underscore the joint role of ID-linked KDMs in regulating cell-type-specific gene silencing and H3K4 methylation levels to safeguard neuronal identity and responsiveness, as well as cognitive function
2025-08-22 | GSE295672 | GEO
Project description:Loss or reduced expression of lysine demethylases (KDMs) is linked to neurodevelopmental disorders and intellectual disability. Given the phenotypic similarities between KDM1A and KDM5C deficient mice, and the convergence of both enzymes in maintaining a repressive state via H3K4 demethylation, we examined their functional interaction using double-inducible, forebrain-specific knockouts (dKDM-ifKOs). These mice showed transcriptional and epigenetic dysregulation beyond the additive effects of individual knockouts, including stronger ectopic expression of non-neuronal genes in hippocampal neurons. Thousands of de novo H3K4me3-enriched regions emerged, indicating synergistic disruption of chromatin regulation. In line with these molecular changes, dKDM-ifKOs displayed more severe behavioral impairments than the single ifKOs, along with altered hippocampal expression of ion channels and increased excitability of CA1 pyramidal neurons. These findings underscore the joint role of ID-linked KDMs in regulating cell-type-specific gene silencing and H3K4 methylation levels to safeguard neuronal identity and responsiveness, as well as cognitive function
2025-08-22 | GSE295536 | GEO
Project description:Transcriptomics analysis of the hippocampus in Kdm1a/Kdm5c double-inducible forebrain-specific knockouts
| PRJNA1255146 | ENA
Project description:Loss or reduced expression of lysine demethylases (KDMs) is linked to neurodevelopmental disorders and intellectual disability. Given the phenotypic similarities between KDM1A and KDM5C deficient mice, and the convergence of both enzymes in maintaining a repressive state via H3K4 demethylation, we examined their functional interaction using double-inducible, forebrain-specific knockouts (dKDM-ifKOs). These mice showed transcriptional and epigenetic dysregulation beyond the additive effects of individual knockouts, including stronger ectopic expression of non-neuronal genes in hippocampal neurons. Thousands of de novo H3K4me3-enriched regions emerged, indicating synergistic disruption of chromatin regulation. In line with these molecular changes, dKDM-ifKOs displayed more severe behavioral impairments than the single ifKOs, along with altered hippocampal expression of ion channels and increased excitability of CA1 pyramidal neurons. These findings underscore the joint role of ID-linked KDMs in regulating cell-type-specific gene silencing and H3K4 methylation levels to safeguard neuronal identity and responsiveness, as well as cognitive function
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Project description:The functional organization of eukaryotic genomes correlates with specific patterns of histone methylations. Regulatory regions in genomes like enhancers and promoters differ in their extent of methylation of histone H3 at lysine-4 (H3K4), but it is largely unknown how the different methylation states are specified and controlled. Here, we show that the Kdm5c/Jarid1c/SMCX member of the Kdm5 family of H3K4 demethylases can be recruited to both enhancer and promoter elements in embryonic stem cells and neuronal progenitor cells via gene-specific transcription factors. Knockdown of Kdm5c deregulates transcription via local increases in H3K4me3. Our data show that restricting H3K4me3 modification at core promoters dampens transcription, but Kdm5c is required at enhancers for their full activity. Remarkably, an impaired enhancer function activates the intrinsic promoter activity of Kdm5c-bound distal elements. Our results demonstrate that the Kdm5c demethylase plays a crucial and dynamic role in the functional discrimination between enhancers and core promoters. RNA from four independent cultures from each sh Kdm5c #1, sh Kdm5c #2 and non-targeting shRNA polyclonal cell lines were hybridized in dye-swap against a common reference of RNA from IB10 ES cells.
2013-04-05 | E-GEOD-38862 | biostudies-arrayexpress
Project description:Here, we show that the Kdm5c/Smcx member of the Jarid1 family of H3K4 demethylases is recruited to both enhancer and core promoter elements in ES and neuronal progenitor cells (NPC). Knockdown of Kdm5c deregulates transcription via a local increase in H3K4me3. While at core promoters the function of Kdm5c is to restrict transcription, loss of Kdm5c impairs enhancer function. Remarkably, an impaired enhancer function activates promoter activity from Kdm5c-bound intergenic regions. Our results demonstrate that the Kdm5c demethylase plays a crucial role in the functional identity and discrimination of enhancers and core promoters. We speculate that this is related to recruitment of H3K4me3 binders like the TFIID and NURF complexes6-8. Providing functional identity to genomic regions through balancing enzymes that deposit and remove histone modifications may prove to be a general epigenetic mechanism for the functional indexing of eukaryotic genomes. Examination of the KDM5C binding sites in mouse embryonic stem cells and in neuronal progenitor cells. Effect of KDM5C knock down on H3K4me3 and H3K4me1 levels and gene expression.
2013-04-01 | E-GEOD-34975 | biostudies-arrayexpress
Project description:Although Kdm1a is the most expressed histone demethylase in neurons, its molecular function in the adult brain remains unknown. Here, we found that inducible and forebrain-restricted knockout (ifKO) mice, in which Kdm1a is specifically eliminated in forebrain excitatory neurons during adulthood, display a prominent transcriptional and epigenomic dysregulation signature characterized by the neuronal expression of nonneuronal genes. The combination of super-resolution microscopy images and multi-omic analysis integrating transcriptome, epigenome and chromatin conformation data showed that these genes are target of the polycomb repressor complex 2 (PRC2) and locate in H3K27me3-microdomains encapsulated within the euchromatin compartment. Furthermore, functional assays revealed that both the catalytic activity and the N-terminus intrinsically disordered region of Kdm1a, which provides phase separation properties, are needed to maintain the boundaries between these silent micro-domains and the active chromatin environment. As a result, Kdm1a loss led to the spreading of active histone modifications into the PRC2-repressed genes causing their de-repression. Intriguingly, the investigation of aged mice suggested that these boundaries may also weaken during natural aging. Overall, these results underscore the role of Kdm1a safeguarding chromatin compartmentalization, nuclear phase separation and gene silencing in the adult and aging brain.
2023-12-04 | GSE236182 | GEO
Project description:RNA from four independent cultures from each sh Kdm5c #1, sh Kdm5c #2 and non-targeting shRNA polyclonal cell lines were hybridized in dye-swap against a common reference of RNA from IB10 ES cells
2013-04-05 | E-MTAB-1177 | biostudies-arrayexpress
Project description:KDM1A requires an adaptor protein with specific DNA-binding activity to recognize chromatin sequence. We constructed HepG2 cells stably overexpressing KDM1A-Flag tag using lentivirus. We performed Co-IP with Flag-gel and we used LC-MS to determine the immunoprecipitates of KDM1A.
2023-05-19 | PXD043284 |
Project description:Chromatin immunoprecipitation (ChIP) experiments were conducted as previously described (Ito et al, 2013) using anti-H3K4me3 (Millipore, #07-473), anti-H3K4me1 (Abcam, #ab8895), or anti-Kdm5C (Iwase et al., 2016). Hippocampi derived from two different animals were pooled together for each sample and two independent biological replicates per condition were sequenced according to manufacturer instructions in a HiSeq2500 apparatus (Illumina, Inc). Information on library preparation method, size of the libraries, and mapping to reference genome can be found in Supplementary Material accompanying the manuscript. ChIP-seq reads were aligned to the mouse genome (Mus_musculus.GRCm.38.83) using bowtie2 (v2.2.9) (Langmead and Salzberg, 2012) and further processed using samtools (v1.3.1) (Li et al., 2009). Peak calling was performed using MACS2 (v2.1.0) (Zhang et al., 2008) with default parameters except for Kdm5c that were as follows: -q 0.01 --nomodel --extsize 131 --broad --broad-cutoff 0.1. Read counts on aligned bam files were performed using Rsubread (v1.22.3) (Liao et al., 2014). Differential peak methylation analysis for H3K4me3 chromatin mark was performed using DESeq2 (v1.10.0) (Love et al., 2014) of the bioconductor suite (Huber et al., 2015) in the R (v3.3) statistical computing platform. For consideration of differentially methylated regions between conditions, we used adjusted p-value < 0.05 as indicated in the manuscript.
2017-08-18 | GSE85873 | GEO