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The KDM5A/RBP2 histone demethylase represses NOTCH signaling to sustain neuroendocrine differentiation and promote small cell lung cancer tumorigenesis

ABSTRACT: The KDM5A/RBP2 histone demethylase represses NOTCH signaling to sustain neuroendocrine differentiation and promote small cell lung cancer tumorigenesis

PROVIDER: PRJNA678685 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13065706.fastq.gz	Fastqsanger.gz
	SRR13065707.fastq.gz	Fastqsanger.gz
	SRR13065708.fastq.gz	Fastqsanger.gz
	SRR13065709.fastq.gz	Fastqsanger.gz
	SRR13065710.fastq.gz	Fastqsanger.gz

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The KDM5A/RBP2 histone demethylase represses NOTCH signaling to sustain neuroendocrine differentiation and promote small cell lung cancer tumorigenesis.

Project description:More than 90% of small cell lung cancers (SCLCs) harbor loss-of-function mutations in the tumor suppressor gene RB1 The canonical function of the RB1 gene product, pRB, is to repress the E2F transcription factor family, but pRB also functions to regulate cellular differentiation in part through its binding to the histone demethylase KDM5A (also known as RBP2 or JARID1A). We show that KDM5A promotes SCLC proliferation and SCLC's neuroendocrine differentiation phenotype in part by sustaining expression of the neuroendocrine transcription factor ASCL1. Mechanistically, we found that KDM5A sustains ASCL1 levels and neuroendocrine differentiation by repressing NOTCH2 and NOTCH target genes. To test the role of KDM5A in SCLC tumorigenesis in vivo, we developed a CRISPR/Cas9-based mouse model of SCLC by delivering an adenovirus (or an adeno-associated virus [AAV]) that expresses Cre recombinase and sgRNAs targeting Rb1, Tp53, and Rbl2 into the lungs of Lox-Stop-Lox Cas9 mice. Coinclusion of a KDM5A sgRNA decreased SCLC tumorigenesis and metastasis, and the SCLCs that formed despite the absence of KDM5A had higher NOTCH activity compared to KDM5A +/+ SCLCs. This work establishes a role for KDM5A in SCLC tumorigenesis and suggests that KDM5 inhibitors should be explored as treatments for SCLC.

| S-EPMC6942053 | biostudies-literature

Histone demethylase RBP2 is critical for breast cancer progression and metastasis

Project description:To determine the roles of RBP2 in breast cancer metastasis, MDA-MD-231 cells were transfected with siRNAs against RBP2 or luciferase control, followed with gene expression microarray analysis and gene set enrichment analysis. These analyses revealed that RBP2 knockdown significantly decreased expression of genes linked to breast cancer metastasis to lung. Total RNA obtained from the breast cancer cell line MDA-MB231 72 hours after transfection with siRNA targeting KDM5A/RBP2/JARID1A, and targeting Luceferase gene as a control.

2014-02-27 | E-GEOD-49119 | biostudies-arrayexpress

The KDM5A/RBP2 histone demethylase represses NOTCH signaling to sustain neuroendocrine differentiation and promote small cell lung cancer tumorigenesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-11-16 | GSE161548 | GEO

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

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

Changes in H3K4 methylation in KDM5A/JARID1A/RBP2 knockout cells.

Project description:We sought to determine H3K4me3 distribution in mouse embryonic stem (ES) cells deficient for RBP2 compared with wild-type cells. RBP2 modifies methylated lysine residues on histone tails. As a result of this analysis, we identified genomic regions with changed H3K4me3 status and described these in gene ontology (GO) categories. Examination of histone methylation in the absence of histone demethylase RBP2

2015-08-12 | E-GEOD-28348 | biostudies-arrayexpress

Genome-wide maps of KDM5A/JARID1A/RBP2 and its isoforms in differentiated U937 cells

Project description:We report the identification of genomic regions bound by RBP2 isoforms and define the functional categories that these regions represent. RBP2 modifies methylated lysine residues on histone tails. We found that RBP2 large isoform containing the recognition module for histone H3K4me3 and RBP2 small isoform lacking this module bind to to different regions in the human genome. Importantly, isoform-specific regions and overlapping regions belong to genes with different molecular functions. For example, chromatin binding and transcription factor binding functions can be ascribed to gene targets of RBP2 small isoform but not of RBP2 large isoform. By comparing gene sets generated for all isoforms and RBP2 large isoform, we can define if the small isoform is specifically recruited to genomic regions dispaying certain signatures, such as transcription start sites, CpG-rich regions, transcriptional activity and transcription factor binding.

2015-03-23 | GSE28323 | GEO

Genome-wide maps of KDM5A/JARID1A/RBP2 and JARID2/JMJ in HL-1 cardiomyocytes.

Project description:We report the identification of genomic regions bound by RBP2 and JARID2 in mouse cardiomyocytes. RBP2 generates methylated lysine 4 in histone H3. Consistent with previous data, RBP2 binds at the TSS regions. However, we found that overepresentation of gene ontologies (GO) for RBP2 targets in cardiomyocytes is drastically different from those in mouse embryonic stem (ES) cells. In cardiomyocytes, there is overepresentation of genes involved in heart morphogenesis and vasculogenesis. Strikingly, we found that location of JARID2, a factor critical for ES cell function, significantly overlaps with RBP2 location in cardiomyocytes.

2018-04-01 | GSE28341 | 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

Genome-wide maps of KDM5A/JARID1A/RBP2 and KDM5B/JARID1B/PLU1 in estrogen treated MCF7 cells.

Project description:We report the identification of genomic regions bound by RBP2 in MCF7 (ER+) cells and the MCF7 cells that were treated with estradiol. RBP2 is recruited to TSS regions and shows preference for GC-rich regions. We find the regions differentially bound by RBP2 after estrogen treatment. These regions will be correlated with binding of ER, H2A.Z and high/low transcriptional activity. We also report genomic regions bound by RBP2 closest homolog, PLU1. PLU1 location does not overlap with RBP2 binding sites. In contrast to RBP2, PLU1 does not show very high enrichment at TSS. This suggests that these two histone demethylases are preferentially located in different regions.

2018-04-01 | GSE28337 | GEO

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