Recruitment of the Mammalian Histone-modifying EMSY Complex to Target Genes Is Regulated by ZNF131
Recent work from others and us revealed interactions between the Sin3/HDAC complex, the H3K4me3 demethylase KDM5A, GATAD1, and EMSY. Here, we characterize the EMSY/KDM5A/SIN3B complex in detail by quantitative interaction proteomics and ChIP-sequencing. We identify a novel substoichiometric interact...
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| Veröffentlicht in: | The Journal of biological chemistry 2016-04, Vol.291 (14), p.7313-7324 |
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| creator | Varier, Radhika A. de Santa Pau, Enrique Carrillo van der Groep, Petra Lindeboom, Rik G.H. Matarese, Filomena Mensinga, Anneloes Smits, Arne H. Edupuganti, Raghu Ram Baltissen, Marijke P. Jansen, Pascal W.T.C. ter Hoeve, Natalie van Weely, Danny R. Poser, Ina van Diest, Paul J. Stunnenberg, Hendrik G. Vermeulen, Michiel |
| description | Recent work from others and us revealed interactions between the Sin3/HDAC complex, the H3K4me3 demethylase KDM5A, GATAD1, and EMSY. Here, we characterize the EMSY/KDM5A/SIN3B complex in detail by quantitative interaction proteomics and ChIP-sequencing. We identify a novel substoichiometric interactor of the complex, transcription factor ZNF131, which recruits EMSY to a large number of active, H3K4me3 marked promoters. Interestingly, using an EMSY knock-out line and subsequent rescue experiments, we show that EMSY is in most cases positively correlated with transcriptional activity of its target genes and stimulates cell proliferation. Finally, by immunohistochemical staining of primary breast tissue microarrays we find that EMSY/KDM5A/SIN3B complex subunits are frequently overexpressed in primary breast cancer cases in a correlative manner. Taken together, these data open venues for exploring the possibility that sporadic breast cancer patients with EMSY amplification might benefit from epigenetic combination therapy targeting both the KDM5A demethylase and histone deacetylases. |
| doi_str_mv | 10.1074/jbc.M115.701227 |
| format | Article |
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Here, we characterize the EMSY/KDM5A/SIN3B complex in detail by quantitative interaction proteomics and ChIP-sequencing. We identify a novel substoichiometric interactor of the complex, transcription factor ZNF131, which recruits EMSY to a large number of active, H3K4me3 marked promoters. Interestingly, using an EMSY knock-out line and subsequent rescue experiments, we show that EMSY is in most cases positively correlated with transcriptional activity of its target genes and stimulates cell proliferation. Finally, by immunohistochemical staining of primary breast tissue microarrays we find that EMSY/KDM5A/SIN3B complex subunits are frequently overexpressed in primary breast cancer cases in a correlative manner. Taken together, these data open venues for exploring the possibility that sporadic breast cancer patients with EMSY amplification might benefit from epigenetic combination therapy targeting both the KDM5A demethylase and histone deacetylases.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M115.701227</identifier><identifier>PMID: 26841866</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; chromatin ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; epidrugs ; epigenetics ; Female ; Gene Knockout Techniques ; Gene Regulation ; genomics ; HeLa Cells ; Histones - genetics ; Histones - metabolism ; Humans ; Multiprotein Complexes - genetics ; Multiprotein Complexes - metabolism ; Neoplasm Proteins - genetics ; Neoplasm Proteins - metabolism ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; proteomics ; Repressor Proteins - genetics ; Repressor Proteins - metabolism ; Retinoblastoma-Binding Protein 2 - genetics ; Retinoblastoma-Binding Protein 2 - metabolism ; transcription ; Transcription Factors - genetics ; Transcription Factors - metabolism</subject><ispartof>The Journal of biological chemistry, 2016-04, Vol.291 (14), p.7313-7324</ispartof><rights>2016 © 2016 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2016 by The American Society for Biochemistry and Molecular Biology, Inc.</rights><rights>2016 by The American Society for Biochemistry and Molecular Biology, Inc. 2016 The American Society for Biochemistry and Molecular Biology, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-1dc08b80d2337a394aee8ae571f7f0e14816e6008064ba0e93f4243aefefd6953</citedby><cites>FETCH-LOGICAL-c509t-1dc08b80d2337a394aee8ae571f7f0e14816e6008064ba0e93f4243aefefd6953</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817164/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817164/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26841866$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Varier, Radhika A.</creatorcontrib><creatorcontrib>de Santa Pau, Enrique Carrillo</creatorcontrib><creatorcontrib>van der Groep, Petra</creatorcontrib><creatorcontrib>Lindeboom, Rik G.H.</creatorcontrib><creatorcontrib>Matarese, Filomena</creatorcontrib><creatorcontrib>Mensinga, Anneloes</creatorcontrib><creatorcontrib>Smits, Arne H.</creatorcontrib><creatorcontrib>Edupuganti, Raghu Ram</creatorcontrib><creatorcontrib>Baltissen, Marijke P.</creatorcontrib><creatorcontrib>Jansen, Pascal W.T.C.</creatorcontrib><creatorcontrib>ter Hoeve, Natalie</creatorcontrib><creatorcontrib>van Weely, Danny R.</creatorcontrib><creatorcontrib>Poser, Ina</creatorcontrib><creatorcontrib>van Diest, Paul J.</creatorcontrib><creatorcontrib>Stunnenberg, Hendrik G.</creatorcontrib><creatorcontrib>Vermeulen, Michiel</creatorcontrib><title>Recruitment of the Mammalian Histone-modifying EMSY Complex to Target Genes Is Regulated by ZNF131</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Recent work from others and us revealed interactions between the Sin3/HDAC complex, the H3K4me3 demethylase KDM5A, GATAD1, and EMSY. Here, we characterize the EMSY/KDM5A/SIN3B complex in detail by quantitative interaction proteomics and ChIP-sequencing. We identify a novel substoichiometric interactor of the complex, transcription factor ZNF131, which recruits EMSY to a large number of active, H3K4me3 marked promoters. Interestingly, using an EMSY knock-out line and subsequent rescue experiments, we show that EMSY is in most cases positively correlated with transcriptional activity of its target genes and stimulates cell proliferation. Finally, by immunohistochemical staining of primary breast tissue microarrays we find that EMSY/KDM5A/SIN3B complex subunits are frequently overexpressed in primary breast cancer cases in a correlative manner. 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Here, we characterize the EMSY/KDM5A/SIN3B complex in detail by quantitative interaction proteomics and ChIP-sequencing. We identify a novel substoichiometric interactor of the complex, transcription factor ZNF131, which recruits EMSY to a large number of active, H3K4me3 marked promoters. Interestingly, using an EMSY knock-out line and subsequent rescue experiments, we show that EMSY is in most cases positively correlated with transcriptional activity of its target genes and stimulates cell proliferation. Finally, by immunohistochemical staining of primary breast tissue microarrays we find that EMSY/KDM5A/SIN3B complex subunits are frequently overexpressed in primary breast cancer cases in a correlative manner. 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| subjects | Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology chromatin DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism epidrugs epigenetics Female Gene Knockout Techniques Gene Regulation genomics HeLa Cells Histones - genetics Histones - metabolism Humans Multiprotein Complexes - genetics Multiprotein Complexes - metabolism Neoplasm Proteins - genetics Neoplasm Proteins - metabolism Nuclear Proteins - genetics Nuclear Proteins - metabolism proteomics Repressor Proteins - genetics Repressor Proteins - metabolism Retinoblastoma-Binding Protein 2 - genetics Retinoblastoma-Binding Protein 2 - metabolism transcription Transcription Factors - genetics Transcription Factors - metabolism |
| title | Recruitment of the Mammalian Histone-modifying EMSY Complex to Target Genes Is Regulated by ZNF131 |
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