Regulation of Sex-biased Gene Expression by the X-Y Chromosomal Gene Pair Kdm5c-Kdm5d in Pluripotent Cells
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ABSTRACT:
PROVIDER: PRJNA1162514 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30714700_1.fastq.gz | Fastqsanger.gz | |||
| SRR30714700_2.fastq.gz | Fastqsanger.gz | |||
| SRR30714701_1.fastq.gz | Fastqsanger.gz | |||
| SRR30714701_2.fastq.gz | Fastqsanger.gz | |||
| SRR30714702_1.fastq.gz | Fastqsanger.gz |
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Project description:Mammalian sex differences are determined by the X and Y chromosomes. Ancestral homologous genes on the sex chromosomes, termed X-Y gene pairs, have been predicted to drive sex differences. However, among the five X-Y gene pairs conserved across eutherians, which pairs drive sex-biased gene expression have remained undefined. Here, we investigate the roles of the X-Y gene pair Kdm5c-Kdm5d in regulating sex-biased gene expression independently of sex hormones using pluripotent mouse embryonic stem cells (ESCs) as a model. Wild-type (WT) XX female and WT XY male ESCs significantly differ in the expression of approximately 4% of all expressed genes, classified as female- or male-biased. Loss of Kdm5c in female ESCs results in the downregulation of female-biased genes. In contrast, loss of either Kdm5c or Kdm5d in male ESCs results in the upregulation of female-biased genes and downregulation of male-biased genes, effectively neutralizing sex-biased gene expression. In male ESCs, most sex-biased genes change in expression in a similar direction upon loss of Kdm5c or Kdm5d. However, Kdm5c loss dysregulates a greater number of sex-biased genes relative to Kdm5d loss in male ESCs. Remarkably, in female ESCs ectopic Kdm5d expression is sufficient to drive a sex-biased gene expression pattern similar to that of WT male ESCs. Taken together, these results establish Kdm5c-Kdm5d as a critical X-Y gene pair in driving sex-biased gene expression in pluripotent cells.
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Project description:KDM5C is commonly mutated in ccRCC tumours in men but rarely in women. Introducing KDM5C mutation into two male and two female KDM5C wild type ccRCC cell lines caused different phenotypes and nonoverlapping transcriptional consequences, indicative of context-dependent functions of KDM5C. We identify that loss of the Y chromosome, harbouring the KDM5C homologue KDM5D, occurs in most male KDM5C mutant ccRCCs. Mutation of KDM5D in male 786-O cells prevented xenograft tumour formation and this phenotype was rescued by co-mutation of KDM5C. This unexpected antagonistic relationship between KDM5C and KDM5D is consistent with the co-occurrence of KDM5C mutation and loss of the Y chromosome in ccRCC. Transcriptional analyses showed that KDM5C and KDM5D regulate the expression of both overlapping as well as distinct sets of genes. Consistent with the tumour growth phenotype, KDM5D mutation induced the upregulation of putative tumour suppressor genes and downregulation of putative pro-proliferative genes. These transcriptional effects were also reversed by co-mutation of KDM5C. While KDM5C and KDM5D bind to at least some overlapping genomic sites, we identify that gene expression changes induced by KDM5C or KDM5D mutation are apparently unrelated to the direct functions of these proteins at the relevant gene promoters or enhancers. Our findings identify similarities and differences in KDM5C and KDM5D functions, challenging the idea that KDM5D in male cells functions equivalently to the second KDM5C allele in female cells, and implicate an interplay between KDM5C mutation and Y chromosome loss in ccRCC development in men.
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Project description:KDM5C is commonly mutated in ccRCC tumours in men but rarely in women. Introducing KDM5C mutation into two male and two female KDM5C wild type ccRCC cell lines caused different phenotypes and nonoverlapping transcriptional consequences, indicative of context-dependent functions of KDM5C. We identify that loss of the Y chromosome, harbouring the KDM5C homologue KDM5D, occurs in most male KDM5C mutant ccRCCs. Mutation of KDM5D in male 786-O cells prevented xenograft tumour formation and this phenotype was rescued by co-mutation of KDM5C. This unexpected antagonistic relationship between KDM5C and KDM5D is consistent with the co-occurrence of KDM5C mutation and loss of the Y chromosome in ccRCC. Transcriptional analyses showed that KDM5C and KDM5D regulate the expression of both overlapping as well as distinct sets of genes. Consistent with the tumour growth phenotype, KDM5D mutation induced the upregulation of putative tumour suppressor genes and downregulation of putative pro-proliferative genes. These transcriptional effects were also reversed by co-mutation of KDM5C. While KDM5C and KDM5D bind to at least some overlapping genomic sites, we identify that gene expression changes induced by KDM5C or KDM5D mutation are apparently unrelated to the direct functions of these proteins at the relevant gene promoters or enhancers. Our findings identify similarities and differences in KDM5C and KDM5D functions, challenging the idea that KDM5D in male cells functions equivalently to the second KDM5C allele in female cells, and implicate an interplay between KDM5C mutation and Y chromosome loss in ccRCC development in men.
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Project description:To uncover novel epigenetic regulators in AML, we performed an in vivo short hairpin RNA (shRNA) screen in the context of Cebpa mutant AML. This led to the identification of the Histone 3 Lysine 4 (H3K4) demethylase, KDM5C, as a novel tumor suppressor in AML. KDM5C potentially functions as a transcriptional repressor via its demethylase activity at promoters, and dysregulation could therefore have widespread consequences. Here, we found that reduced Kdm5c/KDM5C expression is associated with accelerated growth in both human and murine AML cell lines. In vivo, Kdm5c knockdown in a Cebpa mutant AML mouse model resulted in a more aggressive, immature and short-latency phenotype. Mechanistically, we show that knockdown of Kdm5c increased H3K4me3 globally. This translated into the up-regulation of a group of bivalently marked immature genes, resulting in a de-differentiation phenotype which could be reversed by modulating levels of pro-differentiation factors. Finally, we demonstrated that low levels of KDM5C were associated with a decrease in long-term disease-free survival, specifically in female patients. This emphasizes the clinical relevance of our findings and identifies KDM5C as a novel female-biased tumor suppressor in AML.
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