Dataset Information

Genome-wide characterization of BCL6/STAT5-switch target genes identifies reprogramming of DNA damage response as a novel branch of RAC1/PAK1 signalling

ABSTRACT: The RAC1 GTPase and its effector PAK1 have been found to be overexpressed or hyperactivated in colorectal cancer (CRC), one of the most prevalent types of cancer in the world. This overexpression frequently correlates with chemoresistance and less favourable prognoses. We previously showed that the activation of RAC1/PAK1 signalling promotes a switch between the BCL6 transcriptional repressor and the STAT5 transcriptional activator at a subset of pro-proliferative gene promoters. Here we used ChIP-Seq, under conditions of pathway inhibition and stimulation, to identify the BCL6/STAT5-switch binding sites throughout the genome. Using a knowledge-driven pipeline for ChIP-Seq data analysis, we identify 3774 genomic features associated to the switch-motif, with a significant enrichment in protein-coding genes involved in DNA damage repair pathways. Stimulation of RAC1/PAK1 signalling in DLD-1 CRC cells increased the expression of these genes and significantly enhanced DNA repair in response to damage induced by alkylating agents. Our results reveal a new transcriptional reprogramming mechanism whereby the alternate binding of a repressor and an activator protein to low-affinity motifs is used to coordinate a transcriptional response to DNA damage. This mechanism may link the upregulation of the RAC1/PAK1 pathway to the chemoresistant phenotype of aggressive CRCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE97938 | GEO | 2019/04/30

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Sex-dependent pituitary growth hormone (GH) secretory patterns determine the sex-biased expression of >1,000 genes in mouse and rat liver, affecting lipid and drug metabolism, inflammation and disease. A fundamental biological question is how robust differential expression can be achieved for hundreds of sex-biased genes simply based on the GH input signal pattern: pulsatile GH stimulation in males vs. near-continuous GH exposure in females. STAT5 is an essential transcriptional mediator of the sex-dependent effects of GH in the liver, but the mechanisms that underlie its sex-dependent actions are obscure. Here we elucidate the dynamic, sex-dependent binding of STAT5 and the GH/STAT5-regulated repressor BCL6 to mouse liver chromatin, revealing the counteractive interplay between these two regulators of liver sex-specificity. Our findings establish a close correlation between sex-dependent STAT5 binding and sex-biased target gene expression. Moreover, sex-dependent STAT5 binding correlated positively with sex-biased DNase hypersensitivity and H3-K4me1 and H3-K4me3 (activating) marks, correlated negatively with sex-biased H3-K27me3 (repressive) marks, and was associated with sex-differentially enriched motifs for HNF6/CDP factors. Importantly, BCL6 binding was preferentially associated with repression of female-biased STAT5 targets in male liver. Furthermore, BCL6 and STAT5 common targets but not BCL6 unique targets showed strong enrichment for lipid and drug metabolism. These findings provide a comprehensive, genome-wide view of the mechanisms whereby these two GH-regulated transcription factors establish and maintain sex differences affecting liver physiology and disease. The approaches used here to characterize sex-dependent STAT5 and BCL6 binding can be applied to other condition-specific regulatory factors and binding sites and their interplay with co-operative chromatin-binding factors. Mouse livers were excised from individual male and female mice killed at either a peak of STAT5 binding activity, or during the growth hormone (GH) interpulse interval, when STAT5 activity is either low (females) or essentially undetectable (males). Sonicated, cross-linked liver nuclear chromatin was then used to identify STAT5 binding sites by ChIP-Seq.

Dataset Information

Genome-wide characterization of BCL6/STAT5-switch target genes identifies reprogramming of DNA damage response as a novel branch of RAC1/PAK1 signalling

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets