title: Recruitment of the Mammalian Histone-modifying EMSY Complex to Target Genes Is Regulated by ZNF131.
abstract: 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.
authors: From the Department of Molecular Cancer Research, University Medical Center Utrecht, Universiteitsweg 100, 3584CG Utrecht, The Netherlands.
authors: Radhika A
authors: RA
authors: Varier
authors: Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 30, 6525GA Nijmegen, The Netherlands.
authors: Enrique
authors: E
authors: Carrillo de Santa Pau
authors: Department of Pathology, University Medical Center Utrecht Heidelberglaan 100, 3584CX Utrecht, The Netherlands, and.
authors: Petra
authors: P
authors: van der Groep
authors: Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 30, 6525GA Nijmegen, The Netherlands.
authors: Rik G H
authors: RG
authors: Lindeboom
authors: Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 30, 6525GA Nijmegen, The Netherlands.
authors: Filomena
authors: F
authors: Matarese
authors: From the Department of Molecular Cancer Research, University Medical Center Utrecht, Universiteitsweg 100, 3584CG Utrecht, The Netherlands.
authors: Anneloes
authors: A
authors: Mensinga
authors: From the Department of Molecular Cancer Research, University Medical Center Utrecht, Universiteitsweg 100, 3584CG Utrecht, The Netherlands, Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 30, 6525GA Nijmegen, The Netherlands.
authors: Arne H
authors: AH
authors: Smits
authors: Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 30, 6525GA Nijmegen, The Netherlands.
authors: Raghu Ram
authors: RR
authors: Edupuganti
authors: Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 30, 6525GA Nijmegen, The Netherlands.
authors: Marijke P
authors: MP
authors: Baltissen
authors: From the Department of Molecular Cancer Research, University Medical Center Utrecht, Universiteitsweg 100, 3584CG Utrecht, The Netherlands, Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 30, 6525GA Nijmegen, The Netherlands.
authors: Pascal W T C
authors: PW
authors: Jansen
authors: Department of Pathology, University Medical Center Utrecht Heidelberglaan 100, 3584CX Utrecht, The Netherlands, and.
authors: Natalie
authors: N
authors: Ter Hoeve
authors: From the Department of Molecular Cancer Research, University Medical Center Utrecht, Universiteitsweg 100, 3584CG Utrecht, The Netherlands.
authors: Danny R
authors: DR
authors: van Weely
authors: Max Planck Institute of Molecular Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
authors: Ina
authors: I
authors: Poser
authors: Department of Pathology, University Medical Center Utrecht Heidelberglaan 100, 3584CX Utrecht, The Netherlands, and.
authors: Paul J
authors: PJ
authors: van Diest
authors: Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 30, 6525GA Nijmegen, The Netherlands.
authors: Hendrik G
authors: HG
authors: Stunnenberg
authors: From the Department of Molecular Cancer Research, University Medical Center Utrecht, Universiteitsweg 100, 3584CG Utrecht, The Netherlands, Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 30, 6525GA Nijmegen, The Netherlands, m.vermeulen@ncmls.ru.nl.
authors: Michiel
authors: M
authors: Vermeulen
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D055786:Gene Knockout Techniques; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D056485:Retinoblastoma-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C480344:EMSY protein, human; D006657:Histones; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C492042:SIN3B protein, human; D014157:Transcription Factors; C519599:ZNF131 protein, human; C070050:KDM5A protein, human; D056485:Retinoblastoma-Binding Protein 2
keywords: chromatin; epidrugs; epigenetics; gene regulation; genomics; proteomics; transcription