Dataset Information

Hdac3, Setdb1, and Kap1 mark H3K9me3/H3K14ac bivalent regions in young and aged liver.

ABSTRACT: Post-translational modifications of histone tails play a crucial role in gene regulation. Here, we performed chromatin profiling by quantitative targeted mass spectrometry to assess all possible modifications of the core histones. We identified a bivalent combination, a dually marked H3K9me3/H3K14ac modification in the liver, that is significantly decreased in old hepatocytes. Subsequent sequential ChIP-Seq identified dually marked single nucleosome regions, with reduced number of sites and decreased signal in old livers, confirming mass spectrometry results. We detected H3K9me3 and H3K14ac bulk ChIP-Seq signal in reChIP nucleosome regions, suggesting a correlation between H3K9me3/H3K14ac bulk bivalent genomic regions and dually marked single nucleosomes. Histone H3K9 deacetylase Hdac3, as well as H3K9 methyltransferase Setdb1, found in complex Kap1, occupied both bulk and single nucleosome bivalent regions in both young and old livers, correlating to presence of H3K9me3. Expression of genes associated with bivalent regions in young liver, including those regulating cholesterol secretion and triglyceride synthesis, is upregulated in old liver once the bivalency is lost. Hence, H3K9me3/H3K14ac dually marked regions define a poised inactive state that is resolved with loss of one or both of the chromatin marks, which subsequently leads to change in gene expression.

SUBMITTER: Price AJ

PROVIDER: S-EPMC6996956 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Hdac3, Setdb1, and Kap1 mark H3K9me3/H3K14ac bivalent regions in young and aged liver.

Price Andrew J AJ Manjegowda Mohan C MC Kain Jessica J Anandh Swetha S Bochkis Irina M IM

Aging cell 20191219 2

Post-translational modifications of histone tails play a crucial role in gene regulation. Here, we performed chromatin profiling by quantitative targeted mass spectrometry to assess all possible modifications of the core histones. We identified a bivalent combination, a dually marked H3K9me3/H3K14ac modification in the liver, that is significantly decreased in old hepatocytes. Subsequent sequential ChIP-Seq identified dually marked single nucleosome regions, with reduced number of sites and decr ...[more]

PMID: 31858687

Similar Datasets

Project description:BackgroundEpigenetic alterations play an important part in carcinogenesis. Different biological responses, including cell proliferation, migration, apoptosis, invasion, and senescence, are affected by epigenetic alterations in cancer. In addition, growth factors, such as transforming growth factor beta (TGFβ) are important regulators of tumorigenesis. Our understanding of the interplay between the epigenetic bases of tumorigenesis and growth factor signaling in tumorigenesis is rudimentary. Some studies suggest a link between TGFβ signaling and the heterochromatinizing histone mark H3K9me3. There is evidence for signal-dependent interactions between R-Smads and histone methyltransferases. However, the effects of TGFβ signaling on genome wide H3K9me3 landscape remains unknown. Our research examines TGFβ -induced genome-wide H3K9me3 in prostate cancer.MethodChromatin-Immunoprecipitation followed by sequencing was performed to analyze genome-wide association of H3K9me3 epigenetic mark. DAVID Functional annotation tool was utilized to understand the involvement of different Biological Processes and Molecular Function. MEME-ChIP tool was also used to analyze known and novel DNA-binding motifs.ResultsH3K9me3 occupancy appears to increase at intronic regions after short-term (6 hours) TGFβ stimulation and at distal intergenic regions during long-term stimulation (24 hours). We also found evidence for a possible association of SLC transporters with H3K9me3 mark in presence of TGFβ during tumorigenesis. No direct correlation was found between the occupancy of H3K9me3 mark and the expression of various genes. The epigenetic mechanisms-mediated regulation of gene expression by TGFβ was concentrated at promoters rich in SRY and FOXJ3 binding sites.ConclusionOur results point toward a positive association of oncogenic function of TGFβ and the H3K9me3 mark and provide a context to the role of H3K9me3 in TGFβ-induced cell migration and cell adhesion. Interestingly, these functions of TGFβ through H3K9me3 mark regulation seem to depend on transcriptional activation in contrast to the conventionally known repressive nature of H3K9me3.

Project description:BACKGROUND:A multitude of recent studies has observed common epigenetic changes develop in tumour cells of multiple lineages following exposure to stresses such as hypoxia, chemotherapeutics, immunotherapy or targeted therapies. A significant increase in the transcriptionally repressive mark trimethylated H3K9 (H3K9me3) is becoming associated with treatment-resistant phenotypes suggesting upstream mechanisms may be a good target for therapy. We have reported that the increase in H3K9me3 is derived from the methyltransferases SETDB1 and SETDB2 following treatment in melanoma, lung, breast and colorectal cancer cell lines, as well as melanoma patient data. Other groups have observed a number of characteristics such as epigenetic remodelling, increased interferon signalling, cell cycle inhibition and apoptotic resistance that have also been reported by us suggesting these independent studies are investigating similar or identical phenomena. MAIN BODY:Firstly, this review introduces reports of therapy-induced reprogramming in cancer populations with highly similar slow-cycling phenotypes that suggest a role for both IFN signalling and epigenetic remodelling in the acquisition of drug tolerance. We then describe plausible connections between the type 1 IFN pathway, slow-cycling phenotypes and these epigenetic mechanisms before reviewing recent evidence on the roles of SETDB1 and SETDB2, alongside their product H3K9me3, in treatment-induced reprogramming and promotion of drug resistance. The potential mechanisms for the activation of SETDB1 and SETDB2 and how they might arise in treatment is also discussed mechanistically, with a focus on their putative induction by inflammatory signalling. Moreover, we theorise their timely role in attenuating inflammation after their activation in order to promote a more resilient phenotype through homeostatic coordination of H3K9me3. We also examine the relatively uncharacterized functions of SETDB2 with some comparison to the more well-known qualities of SETDB1. Finally, an emerging overall mechanism for the epigenetic maintenance of this transient phenotype is outlined by summarising the collective literature herein. CONCLUSION:A number of converging phenotypes outline a stress-responsive mechanism for SETDB1 and SETDB2 activation and subsequent increased survival, providing novel insights into epigenetic biology. A clearer understanding of how SETDB1/2-mediated transcriptional reprogramming can subvert treatment responses will be invaluable in improving length and efficacy of modern therapies.

Dataset Information

Hdac3, Setdb1, and Kap1 mark H3K9me3/H3K14ac bivalent regions in young and aged liver.

Publications

Hdac3, Setdb1, and Kap1 mark H3K9me3/H3K14ac bivalent regions in young and aged liver.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets