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

• Published in: PLOS Genetics
• Main Authors: Kenny, Colin, Dilshat, Ramile, Seberg, Hannah E., Van Otterloo, Eric, Bonde, Gregory, Helverson, Annika, Franke, Christopher M., Steingrímsson, Eiríkur, Cornell, Robert A.
• Other Authors: Faculty of Medicine, University of Iceland
• Format: Article in Journal/Newspaper
• Language: English
• Published: 2022
• Subjects: Ecology; Evolution; Behavior and Systematics; Molecular Biology; Genetics; Genetics (clinical); Cancer Research; Iceland
• Online Access: https://hdl.handle.net/20.500.11815/3800; https://doi.org/10.1371/journal.pgen.1010207

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. 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. ...