Proteasome inhibition creates a chromatin landscape favorable to RNA Pol II processivity
| Autor: | Pierre R. Bushel, H. Karimi Kinyamu, Brian D. Bennett, Trevor K. Archer |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Proteasome Endopeptidase Complex Transcription Genetic Leupeptins RNA polymerase II Biology Biochemistry Epigenesis Genetic Histones 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Protein Domains Transcription (biology) RNA polymerase Gene expression medicine Humans Gene Regulation RNA Messenger Phosphorylation Promoter Regions Genetic Molecular Biology RNA Acetylation Cell Biology Processivity Chromatin Assembly and Disassembly Chromatin Nucleosomes Cell biology Gene Expression Regulation Neoplastic 030104 developmental biology chemistry 030220 oncology & carcinogenesis MCF-7 Cells Proteasome inhibitor biology.protein Chromatin Immunoprecipitation Sequencing RNA Polymerase II Transcription Initiation Site Proteasome Inhibitors medicine.drug |
| Zdroj: | J Biol Chem |
| ISSN: | 1083-351X 0021-9258 |
| DOI: | 10.1074/jbc.ra119.011174 |
| Popis: | Proteasome activity is required for diverse cellular processes, including transcriptional and epigenetic regulation. However, inhibiting proteasome activity can lead to an increase in transcriptional output that is correlated with enriched levels of trimethyl H3K4 and phosphorylated forms of RNA polymerase (Pol) II at the promoter and gene body. Here, we perform gene expression analysis and ChIP followed by sequencing (ChIP-seq) in MCF-7 breast cancer cells treated with the proteasome inhibitor MG132, and we further explore genome-wide effects of proteasome inhibition on the chromatin state and RNA Pol II transcription. Analysis of gene expression programs and chromatin architecture reveals that chemically inhibiting proteasome activity creates a distinct chromatin state, defined by spreading of the H3K4me3 mark into the gene bodies of differentially-expressed genes. The distinct H3K4me3 chromatin profile and hyperacetylated nucleosomes at transcription start sites establish a chromatin landscape that facilitates recruitment of Ser-5- and Ser-2–phosphorylated RNA Pol II. Subsequent transcriptional events result in diverse gene expression changes. Alterations of H3K36me3 levels in the gene body reflect productive RNA Pol II elongation of transcripts of genes that are induced, underscoring the requirement for proteasome activity at multiple phases of the transcriptional cycle. Finally, by integrating genomics data and pathway analysis, we find that the differential effects of proteasome inhibition on the chromatin state modulate genes that are fundamental for cancer cell survival. Together, our results uncover underappreciated downstream effects of proteasome inhibitors that may underlie targeting of distinct chromatin states and key steps of RNA Pol II–mediated transcription in cancer cells. |
| Databáze: | OpenAIRE |
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