Unknown,Transcriptomics,Genomics,Proteomics

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High Mobility Group protein mediated transcription requires DNA damage marker Î³-H2AX

ABSTRACT: The eukaryotic genome is organized into chromatin, which constitutes the physiological template for DNA-dependent processes including replication, recombination, repair and transcription. Chromatin mediated transcription regulation involves histone modifications, chromatin remodeling and DNA methylation. However, the precise biological function of non-histone chromatin-associated proteins is still unclear. The high mobility group proteins are the most abundant non-histone chromatin-associated proteins. Here we combined proteomic, ChIP-seq and transcriptome data to decipher the mechanism of transcriptional regulation mediated by the high mobility group AT-hook protein 2 (HMGA2). We showed that HMGA2-induced transcription requires H2AX phosphorylation at S139 (H2AXS139ph; Î³-H2AX), mediated by the kinase ataxia telangiectasia mutated (ATM). Furthermore, we demonstrated the relevance of this mechanism within the biological context of TGFB1-signaling. Our results link H2AXS139ph, a marker for DNA damage, to transcription, which is a new function for this histone modification. The interplay between HMGA2, ATM and H2AX is a novel mechanism of transcription initiation. Chip-seq data of HMGA2, H2AXS139ph and ATM obtained from Mouse embryonic Fibroblast cells in wt and Ko of Hmga2

ORGANISM(S): Mus musculus

SUBMITTER: Guillermo Barreto

PROVIDER: E-GEOD-63861 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:In Saccharomyces cerevisiae, a single double-strand break (DSB) triggers extensive phosphorylation of histone H2A (known as gammaH2AX) over 50 kb on either side of the DSB. This modification is carried out by either of yeastM-^Rs checkpoint kinases, the ATM homolog, Tel1, or the ATR homolog, Mec1. In G1-arrested cells, where there is very little 5M-^R to 3M-^R processing of DSB ends, only Tel1 promotes this modification. We have recently described a second modification gammaH2B - the phosphorylation of the C terminal T129 locus of histone H2B which is also carried out by both Mec1 and Tel1 kinases. To understand in detail how gamma-H2AX and gamma-H2B spread along the chromosome from a DSB we have undertaken a high-density analysis of their occupancy where there is a DSB on three different chromosomes. gamma-H2AX and gamma-H2B modifications are similar, but there is a marked absence of gamma-H2B near telomeres. We find that there is reduced gamma-H2AX and gamma-H2B modification over strongly transcribed regions, even taking into account the reduced histone occupancy of these genes. When transcription of the galactose-regulated genes GAL1, GAL10, GAL7 are turned off by the addition of glucose, gamma-H2AX is restored within 5 min; when these genes are again induced, gamma-H2AX is rapidly lost. Regions more distal to the GAL genes have markedly reduced gamma-H2AX levels that rise rapidly when transcription is repressed, suggesting that transcription acts as a barrier to the propagation of gamma-H2AX away from the DSB. The restoration of gamma-H2AX in transcribed regions can be carried out by either Mec1 or Tel1, even 7 h after break induction, suggesting that Tel1 remains associated with damaged chromosomes for an extended time. In addition, we show that gamma-H2AX can be transferred in trans, to regions unlinked to the DSB that lie in close proximity the DSB. Specifically, if a DSB is generated 14 kb from CEN2, gamma-H2AX is transferred to regions around all the other centromeres, in keeping with observed close proximity of all centromere-adjacent chromosome arms. This transfer can be observed even in the absence of formaldehyde crosslinking of the samples.

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High Mobility Group protein mediated transcription requires DNA damage marker Î³-H2AX

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