JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states
The bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylate...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2018-04-01
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| Series: | Epigenetics |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15592294.2018.1469891 |
| _version_ | 1797678904980275200 |
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| author | Lusy Handoko Bogumil Kaczkowski Chung-Chau Hon Marina Lizio Masatoshi Wakamori Takayoshi Matsuda Takuhiro Ito Prashanti Jeyamohan Yuko Sato Kensaku Sakamoto Shigeyuki Yokoyama Hiroshi Kimura Aki Minoda Takashi Umehara |
| author_facet | Lusy Handoko Bogumil Kaczkowski Chung-Chau Hon Marina Lizio Masatoshi Wakamori Takayoshi Matsuda Takuhiro Ito Prashanti Jeyamohan Yuko Sato Kensaku Sakamoto Shigeyuki Yokoyama Hiroshi Kimura Aki Minoda Takashi Umehara |
| author_sort | Lusy Handoko |
| collection | DOAJ |
| description | The bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylated chromatin is not understood at the genome-wide level. Here, we report transcription start site (TSS)-resolution integrative analyses of ChIP-seq and transcriptome profiles in human non-small cell lung cancer (NSCLC) cell line H23. We show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Although BET inhibition by JQ1 led to complete reduction of BRD2 binding to chromatin, only local changes of H4K5acK8ac levels were observed, suggesting that recruitment of BRD2 does not influence global histone H4 hyperacetylation levels. This finding supports a model in which recruitment of BET proteins via histone H4 hyperacetylation is predominant over hyperacetylation of histone H4 by BET protein-associated acetyltransferases. In addition, we found that a remarkable number of BRD2-bound genes, including MYC and its downstream target genes, were transcriptionally upregulated upon JQ1 treatment. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors potentially involved in the JQ1 response in BRD2-dependent and -independent manner. |
| first_indexed | 2024-03-11T23:06:43Z |
| format | Article |
| id | doaj.art-a5a3e24b8e2b44a8ae4456359d3ec093 |
| institution | Directory Open Access Journal |
| issn | 1559-2294 1559-2308 |
| language | English |
| last_indexed | 2024-03-11T23:06:43Z |
| publishDate | 2018-04-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Epigenetics |
| spelling | doaj.art-a5a3e24b8e2b44a8ae4456359d3ec0932023-09-21T13:09:20ZengTaylor & Francis GroupEpigenetics1559-22941559-23082018-04-0113441043110.1080/15592294.2018.14698911469891JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin statesLusy Handoko0Bogumil Kaczkowski1Chung-Chau Hon2Marina Lizio3Masatoshi Wakamori4Takayoshi Matsuda5Takuhiro Ito6Prashanti Jeyamohan7Yuko Sato8Kensaku Sakamoto9Shigeyuki Yokoyama10Hiroshi Kimura11Aki Minoda12Takashi Umehara13RIKEN Center for Life Science Technologies, YokohamaRIKEN Center for Life Science Technologies, YokohamaRIKEN Center for Life Science Technologies, YokohamaRIKEN Center for Life Science Technologies, YokohamaRIKEN Center for Life Science Technologies, YokohamaRIKEN Center for Life Science Technologies, YokohamaRIKEN Center for Life Science Technologies, YokohamaRIKEN Center for Life Science Technologies, YokohamaTokyo Institute of Technology, YokohamaRIKEN Center for Life Science Technologies, YokohamaRIKEN Structural Biology Laboratory, YokohamaTokyo Institute of Technology, YokohamaRIKEN Center for Life Science Technologies, YokohamaRIKEN Center for Life Science Technologies, YokohamaThe bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylated chromatin is not understood at the genome-wide level. Here, we report transcription start site (TSS)-resolution integrative analyses of ChIP-seq and transcriptome profiles in human non-small cell lung cancer (NSCLC) cell line H23. We show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Although BET inhibition by JQ1 led to complete reduction of BRD2 binding to chromatin, only local changes of H4K5acK8ac levels were observed, suggesting that recruitment of BRD2 does not influence global histone H4 hyperacetylation levels. This finding supports a model in which recruitment of BET proteins via histone H4 hyperacetylation is predominant over hyperacetylation of histone H4 by BET protein-associated acetyltransferases. In addition, we found that a remarkable number of BRD2-bound genes, including MYC and its downstream target genes, were transcriptionally upregulated upon JQ1 treatment. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors potentially involved in the JQ1 response in BRD2-dependent and -independent manner.http://dx.doi.org/10.1080/15592294.2018.1469891betbrd2cageh4 hyperacetylationjq1 |
| spellingShingle | Lusy Handoko Bogumil Kaczkowski Chung-Chau Hon Marina Lizio Masatoshi Wakamori Takayoshi Matsuda Takuhiro Ito Prashanti Jeyamohan Yuko Sato Kensaku Sakamoto Shigeyuki Yokoyama Hiroshi Kimura Aki Minoda Takashi Umehara JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states Epigenetics bet brd2 cage h4 hyperacetylation jq1 |
| title | JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states |
| title_full | JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states |
| title_fullStr | JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states |
| title_full_unstemmed | JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states |
| title_short | JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states |
| title_sort | jq1 affects brd2 dependent and independent transcription regulation without disrupting h4 hyperacetylated chromatin states |
| topic | bet brd2 cage h4 hyperacetylation jq1 |
| url | http://dx.doi.org/10.1080/15592294.2018.1469891 |
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