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ChIP-seq analyses for KDM5A, H3K4me3, RNAPII and TAF3 in human multiple myeloma cell line MM.1S

ABSTRACT: Recent studies have highlighted the oncogenic roles of KDM5A; however, its molecular mechanism has not been fully delineated. Here we identifies KDM5A as a transcriptional activator of MYC target genes in multiple myeloma (MM). Genetic ablation of KDM5A or pharmacologic inhibition of KDM5 by novel inhibitor JQKD82 impairs MM cell growth. Gene expression profile reveals that JQKD82 decreases expression of MYC targets. Expression of MYC targets is similarly downregulated by KDM5A depletion, but little affected by KDM5B knockdown. Mechanistically, KDM5A co-localizes with MYC across the genome, and KDM5A and MYC coordinately promote MYC target gene transcription. The treatment with JQKD82 reduces phosphorylation level of RNA polymerase II (RNAPII), resulting in RNAPII pausing, accompanied by hyper-H3K4me3 status at the MYC loci. Finally, we shows that JQKD82 exerts anti-MM activity and prolongs overall survival in vivo mouse xenograft models. Our results delineate KDM5A function that reinforces MYC transcriptional program, and identify KDM5A as a potential therapeutic target in MM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148046 | GEO | 2021/03/22

REPOSITORIES: GEO

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RNA-seq analysis after JQKD82 treatment in human multiple myeloma cell line MM.1S

Project description:Recent studies have highlighted the oncogenic roles of KDM5A; however, its molecular mechanism has not been fully delineated. Here we identifies KDM5A as a transcriptional activator of MYC target genes in multiple myeloma (MM). Genetic ablation of KDM5A or pharmacologic inhibition of KDM5 by novel inhibitor JQKD82 impairs MM cell growth. Gene expression profile reveals that JQKD82 decreases expression of MYC targets. Expression of MYC targets is similarly downregulated by KDM5A depletion, but little affected by KDM5B knockdown. Mechanistically, KDM5A co-localizes with MYC across the genome, and KDM5A and MYC coordinately promote MYC target gene transcription. The treatment with JQKD82 reduces phosphorylation level of RNA polymerase II (RNAPII), resulting in RNAPII pausing, accompanied by hyper-H3K4me3 status at the MYC loci. Finally, we shows that JQKD82 exerts anti-MM activity and prolongs overall survival in vivo mouse xenograft models. Our results delineate KDM5A function that reinforces MYC transcriptional program, and identify KDM5A as a potential therapeutic target in MM.

2021-03-22 | GSE148047 | GEO

ChIP-seq and RNA-seq analyses in human multiple myeloma cell line MM.1S

2021-03-22 | GSE148048 | GEO

ChIP-seq analyses for KDM5A, H3K4me3, RNAPII and TAF3 in human multiple myeloma cell line MM.1S

Project description:ChIP-seq analyses for KDM5A, H3K4me3, RNAPII and TAF3 in human multiple myeloma cell line MM.1S

| PRJNA622960 | ENA

KDM5A suppresses PML-RARα target gene expression and APL differentiation through repressing H3K4me2

Project description:Epigenetic abnormalities are frequently involved in the initiation and progression of cancers including acute myeloid leukemia (AML). A subtype of AML, Acute promyelocytic leukemia (APL), is mainly driven by a specific oncogenic fusion event of PML-RARα. PML-RARα was reported as a transcription repressor through the interaction with NCoR/HDAC complexes leading to the mis-suppression of its target genes and differentiation blockage. While previous studies were mainly focused on the connection of histone acetylation, it is still largely unknown whether alternative epigenetics mechanisms are involved in APL progression. KDM5A is a demethylase of histone H3 lysine 4 di- and tri- methylations (H3K4me2/3) and a transcription corepressor. Here, we found that the loss of KDM5A led to APL NB4 cell differentiation and retarded growth. Mechanistically, through epigenomics and transcriptomics analyses, we detected KDM5A binding in 1,889 genes, with the majority of the binding events at promoter regions. KDM5A suppressed the expression of 621 genes, including 42 PML-RARα target genes primarily by controlling the H3K4me2 in the promoters and 5’ end intragenic regions. In addition, a recently reported pan-KDM5 inhibitor, CPI-455 on its own could phenocopy the differentiation effects as KDM5A loss in NB4 cells. CPI-455 treatment or KDM5A knockout could greatly sensitize NB4 cells to ATRA induced differentiation. Our findings indicated that KDM5A contributed to the differentiation blockage in the APL cell line NB4, and inhibition of KDM5A could greatly potentiate NB4 differentiation.

2021-04-01 | GSE152397 | GEO

Profiling non-small cell lung carcinoma cell line PC9 treated with erlotinib, KDM5A inhibitor, or viruses expressing KDM5 shRNAs or cDNA

Project description:The non-small cell lung carcinoma (NSCLC) PC9 cell line is an established preclinical model for tyrosine kinase inhibitors. Recent evidence suggests that KDM5A protein is required for emerging drug-resistant cell population. To better understand the dependence of cell survival on KDM5A, we treated EGFR-mutant PC9 cells with erlotinib, KDM5A inhibitor or KDM5A and KDM5B shRNAs and performed Drop-seq. We were able to clearly distinguish cells with KDM5A knockdown from cells with KDM5A overexpression. We were able to identify specific biomarkers associated with varying dose of KDM5A, for each cell population. The results of this study will address clinical usefulness of KDM5A-targeted strategies in overcoming drug resistance, particularly in NSCLC.

2022-07-25 | GSE134840 | GEO

Genome-wide maps of KDM5A/JARID1A/RBP2 in mouse ES cells.

Project description:We report the identification of genomic regions bound by KDM5A in mouse embryonic stem (ES) cells and define the functional categories that these regions represent. KDM5A modifies methylated lysine residues on histone tails. We developed anti-KDM5A antibodies and set to detect genomic regions enriched with these antibodies using cells with normal Kdm5a or cells from Kdm5a knockout mice as a control. We found high enrichment with the KDM5A antibodies in normal cells when compared with the genomic background. We found striking identity in the regions enriched with these antibodies in normal cells when compared with the total genomic DNA or with KDM5A ChIP assays from Kdm5a KO cells, showing that the antibodies are specific. Examination of target genes in ES cells

2012-10-04 | E-GEOD-28343 | biostudies-arrayexpress

Gene expression profiles of KDM5A-/- MEFs with wild-type KDM5A or KDM5A-H483A mutant

Project description:Gene expression profiles of Immortalized KDM5A-/- MEFs with re-introduction of wild-type KDM5A or KDM5A-H483A mutant.

2017-02-08 | GSE84309 | GEO

Impaired transcriptional profile in the hippocampus following loss of Kdm5a

Project description:KDM5A encodes a histone lysine demethylase that removes methyl groups from lysine 4 of histone H3, resulting in repression of target genes. In order to identify KDM5A targets, we profiled transcripts from hippocampi of WT and Kdm5a -/- mice. Loss of KDM5A resulted in dysregulation of 450 genes (FDR-corrected P ≤0.05 and log2 fold change ≥|0.3|), of which 191 genes were upregulated and 259 genes were downregulated.

2020-12-14 | GSE147435 | GEO

Genome-wide KDM5A occupancy after MK2206/DMSO treatment of T47D cells

Project description:We perfomed ChIP-seq using KDM5A antibodies in T47D cells after 24 hour treatment with the AKT inhibitor MK2206 or DMSO. We show that the cistrome of the H3K4 demethylase KDM5A is affected by AKT inhibition. Comparison of genome-wide KDM5A binding after AKT inhibition vs vehicle

2016-06-14 | E-GEOD-80593 | biostudies-arrayexpress

Myogeneic differentiation in Rb1 or Kdm5a/Jarid1a/Rbp2 deficient mouse embryonic fibroblasts.

Project description:Cells lacking Rb1 are deficient in differentiation. Loss of Kdm5a rescues myogenic differentiation, as judged by appearance of morphologically normal myotubes that display expression of late markers of differentiation. In order to better understand how Kdm5a loss rescues differentiation, we induced mouse embryonic fibroblasts (MEFs) of different genotypes to undergo myogenic differentiation and analyzed gene expression changes in wild-type, Kdm5a-/-, Rb1-/- and Kdm5a-/-; Rb1-/- cells. Rb1-/- cells stained single nucleated, did not exhibit morphological changes and increased expression of the myogenic marker MYHC. Except for Rb1-/- cells, all other cells were undergoing successful convertion into aligned multinucleated myotubes and were MYHC-positive. We obtained purified populations of myotubes for the wild-type and Kdm5a-/-; Rb1-/- cells. RNA-seq analysis of gene expression in Rb1 or Kdm5a deficient MEFs that were induced for myogenic differentiation.

2015-08-12 | E-GEOD-53528 | biostudies-arrayexpress

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