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The Kdm5c histone demethylase controls enhancer and promoter function.

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE34975 | GEO | 2013/04/01

SECONDARY ACCESSION(S): PRJNA151105

REPOSITORIES: GEO

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The Kdm5c histone demethylase controls enhancer and promoter function.

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

NO001: Kdm5c controls promoter and enhancer activities

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

NO001: Kdm5c controls promoter and enhancer activities

2013-04-05 | GSE38862 | GEO

Activation of Xist by An Evolutionarily Conserved Function of the KDM5C Demethylase

Project description:We performed Kdm5c (Smcx) ChIP-Seq in del_Tsix XY mouse epiblast cells with two genotypes: Smcx-WT and Smcx-KO

2022-04-14 | GSE96740 | GEO

Targeting H3K4 methylation as a therapeutic strategy for Huntington's disease (ChIP-seq)

Project description:Transcriptional dysregulation is an early feature of Huntington's disease (HD). We observed gene-specific changes in H3K4me3 at transcriptionally repressed promoters in R6/2 mouse and human HD brain. Genome-wide analysis showed a novel chromatin signature for this mark. Reducing the levels of the H3K4 demethylase SMCX/Jarid1c in primary neurons reversed down-regulation of key neuronal genes caused by mutant Huntingtin (Htt) expression. Finally, reduction of SMCX/Jarid1c in primary neurons from BACHD mice or the single Jarid1 in a Drosophila HD model was protective. Therefore, targeting this epigenetic signature may be an effective strategy to ameliorate the consequences of HD. ChIP-seq for H3K4me3 in wild type and R6/2 cortex and striatum at 8 and 12 weeks.

2013-07-18 | E-GEOD-48960 | biostudies-arrayexpress

Targeting H3K4 methylation as a therapeutic strategy for Huntington's disease (RNA-seq)

2013-07-18 | GSE48962 | GEO

Targeting H3K4 methylation as a therapeutic strategy for Huntington's disease (ChIP-seq)

2013-07-18 | GSE48960 | GEO

Targeting H3K4 methylation as a therapeutic strategy for Huntington's disease (RNA-seq)

Project description:Transcriptional dysregulation is an early feature of Huntington's disease (HD). We observed gene-specific changes in H3K4me3 at transcriptionally repressed promoters in R6/2 mouse and human HD brain. Genome-wide analysis showed a novel chromatin signature for this mark. Reducing the levels of the H3K4 demethylase SMCX/Jarid1c in primary neurons reversed down-regulation of key neuronal genes caused by mutant Huntingtin (Htt) expression. Finally, reduction of SMCX/Jarid1c in primary neurons from BACHD mice or the single Jarid1 in a Drosophila HD model was protective. Therefore, targeting this epigenetic signature may be an effective strategy to ameliorate the consequences of HD. mRNA-seq in wild type and R6/2 cortex and striatum at 8 and 12 weeks.

2013-07-18 | E-GEOD-48962 | biostudies-arrayexpress

Aggression, cognitive and neurodevelopmental abnormalities associated with disruption of the intellectual disability and histone demethylase gene Kdm5c.

Project description:We conducted ChIP-Seq of KDM5c in neurons isolated from E16.5 mouse embryonic cortices from WT and SMCX KO mice and harvested after 10 days in vitro culture.

2016-01-27 | GSE75866 | GEO

A Surveillance System of Active Enhancers by a RACK7-histone Demethylase Complex (ChIP-Seq I)

Project description:Primed enhancers are marked by histone H3K4 mono-methylation (H3K4me1), and the conversion to active enhancers involves acetylation of histone H3K27 (H3K27Ac). However, whether active enhancers are regulated remains unclear. Here we report a biochemical complex consisting of a potential chromatin reader (RACK7) and a histone demethylase (KDM5C) that occupies many active enhancers in a breast cancer cell line. Loss of RACK7 or KDM5C results in hyperactive enhancers marked by H3K4me3 and H3K27Ac, and characterized by an increased eRNA transcription and elevated expression of nearby genes. Loss of RACK7 or KDM5C also leads to increased cell invasion and migration, and enhanced tumor growth. We propose that RACK7/KDM5C functions as an enhancer âbrakeâ to ensure appropriate enhancer activities in the cell. Our findings provide important insight into histone H3K4 methylation dynamics at enhancers and reveal a molecular mechanism that controls the activities of active enhancers, which when compromised, can contribute to tumorigenesis. ChIP-seq data of RACK7, KDM5C and histone modifications in parental and RACK7-KO ZR-75-30 cells.

2016-04-07 | E-GEOD-71323 | biostudies-arrayexpress

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