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TFAP2 paralogs facilitate chromatin access for MITF at pigmentation and cell proliferation genes

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dc.contributor University of Iceland
dc.contributor.author Kenny, Colin
dc.contributor.author Dilshat, Ramile
dc.contributor.author Seberg, Hannah E.
dc.contributor.author Van Otterloo, Eric
dc.contributor.author Bonde, Gregory
dc.contributor.author Helverson, Annika
dc.contributor.author Franke, Christopher M.
dc.contributor.author Steingrímsson, Eiríkur
dc.contributor.author Cornell, Robert A.
dc.date.accessioned 2022-12-28T01:04:04Z
dc.date.available 2022-12-28T01:04:04Z
dc.date.issued 2022-05-17
dc.identifier.citation Kenny , C , Dilshat , R , Seberg , H E , Van Otterloo , E , Bonde , G , Helverson , A , Franke , C M , Steingrímsson , E & Cornell , R A 2022 , ' TFAP2 paralogs facilitate chromatin access for MITF at pigmentation and cell proliferation genes ' , PLoS Genetics , vol. 18 , no. 5 , e1010207 , pp. e1010207 . https://doi.org/10.1371/journal.pgen.1010207
dc.identifier.issn 1553-7390
dc.identifier.other PURE: 69087107
dc.identifier.other PURE UUID: e0cf0b25-607f-4b8f-87a2-159965590980
dc.identifier.other Scopus: 85131268724
dc.identifier.uri https://hdl.handle.net/20.500.11815/3800
dc.description Funding Information: This work was supported by grants from the National Institutes of Health (NIH) to RAC (R01-AR062457), a postdoctoral fellowship from the American Association for Anatomy to CK, and grants from the Research Fund of Iceland to ES (207067 & 217768). https://grants.nih.gov/grants/ funding/r01.htm https://www.anatomy.org https:// en.rannis.is/funding/research/icelandic-researchfund/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2022 Kenny et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.description.abstract In developing melanocytes and in melanoma cells, multiple paralogs of the Activating-enhancer-binding Protein 2 family of transcription factors (TFAP2) contribute to expression of genes encoding pigmentation regulators, but their interaction with Microphthalmia transcription factor (MITF), a master regulator of these cells, is unclear. Supporting the model that TFAP2 facilitates MITF's ability to activate expression of pigmentation genes, single-cell seq analysis of zebrafish embryos revealed that pigmentation genes are only expressed in the subset of mitfa-expressing cells that also express tfap2 paralogs. To test this model in SK-MEL-28 melanoma cells we deleted the two TFAP2 paralogs with highest expression, TFAP2A and TFAP2C, creating TFAP2 knockout (TFAP2-KO) cells. We then assessed gene expression, chromatin accessibility, binding of TFAP2A and of MITF, and the chromatin marks H3K27Ac and H3K27Me3 which are characteristic of active enhancers and silenced chromatin, respectively. Integrated analyses of these datasets indicate TFAP2 paralogs directly activate enhancers near genes enriched for roles in pigmentation and proliferation, and directly repress enhancers near genes enriched for roles in cell adhesion. Consistently, compared to WT cells, TFAP2-KO cells proliferate less and adhere to one another more. TFAP2 paralogs and MITF co-operatively activate a subset of enhancers, with the former necessary for MITF binding and chromatin accessibility. By contrast, TFAP2 paralogs and MITF do not appear to co-operatively inhibit enhancers. These studies reveal a mechanism by which TFAP2 profoundly influences the set of genes activated by MITF, and thereby the phenotype of pigment cells and melanoma cells.
dc.format.extent e1010207
dc.language.iso en
dc.relation.ispartofseries PLoS Genetics; 18(5)
dc.rights info:eu-repo/semantics/openAccess
dc.subject Ecology, Evolution, Behavior and Systematics
dc.subject Molecular Biology
dc.subject Genetics
dc.subject Genetics (clinical)
dc.subject Cancer Research
dc.title TFAP2 paralogs facilitate chromatin access for MITF at pigmentation and cell proliferation genes
dc.type /dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article
dc.description.version Peer reviewed
dc.identifier.pmid 35580127
dc.identifier.doi https://doi.org/10.1371/journal.pgen.1010207
dc.relation.url http://www.scopus.com/inward/record.url?scp=85131268724&partnerID=8YFLogxK
dc.contributor.department Faculty of Medicine

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