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HMGN2 represses gene transcription via interaction with transcription factors Lef-1 and Pitx2 during amelogenesis.
Eliason, Steven; Su, Dan; Pinho, Flavia; Sun, Zhao; Zhang, Zichao; Li, Xiao; Sweat, Mason; Venugopalan, Shankar R; He, Bing; Bustin, Michael; Amendt, Brad A.
Affiliation
  • Eliason S; Department of Anatomy and Cell Biology and the Craniofacial Anomalies Research Center, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA.
  • Su D; Department of Anatomy and Cell Biology and the Craniofacial Anomalies Research Center, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA.
  • Pinho F; Janssen R&D, LLC, San Diego, California, USA.
  • Sun Z; Washington University St Louis, St Louis, Missouri, USA.
  • Zhang Z; Institute for Biosciences and Technology, Houston, Texas, USA.
  • Li X; Texas Heart Institute, Houston, Texas, USA.
  • Sweat M; Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Venugopalan SR; Department of Orthodontics, The University of Iowa, Iowa City, Iowa, USA.
  • He B; Protein Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Bustin M; Protein Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Amendt BA; Department of Anatomy and Cell Biology and the Craniofacial Anomalies Research Center, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA; Department of Orthodontics, The University of Iowa, Iowa City, Iowa, USA. Electronic address: brad-amendt@uiowa.edu.
J Biol Chem ; 298(9): 102295, 2022 09.
Article in En | MEDLINE | ID: mdl-35872015
ABSTRACT
The chromatin-associated high mobility group protein N2 (HMGN2) cofactor regulates transcription factor activity through both chromatin and protein interactions. Hmgn2 expression is known to be developmentally regulated, but the post-transcriptional mechanisms that regulate Hmgn2 expression and its precise roles in tooth development remain unclear. Here, we demonstrate that HMGN2 inhibits the activity of multiple transcription factors as a general mechanism to regulate early development. Bimolecular fluorescence complementation, pull-down, and coimmunoprecipitation assays show that HMGN2 interacts with the transcription factor Lef-1 through its HMG-box domain as well as with other early development transcription factors, Dlx2, FoxJ1, and Pitx2. Furthermore, EMSAs demonstrate that HMGN2 binding to Lef-1 inhibits its DNA-binding activity. We found that Pitx2 and Hmgn2 associate with H4K5ac and H3K4me2 chromatin marks in the proximal Dlx2 promoter, demonstrating Hmgn2 association with open chromatin. In addition, we demonstrate that microRNAs (miRs) mir-23a and miR-23b directly target Hmgn2, promoting transcriptional activation at several gene promoters, including the amelogenin promoter. In vivo, we found that decreased Hmgn2 expression correlates with increased miR-23 expression in craniofacial tissues as the murine embryo develops. Finally, we show that ablation of Hmgn2 in mice results in increased amelogenin expression because of increased Pitx2, Dlx2, Lef-1, and FoxJ1 transcriptional activity. Taken together, our results demonstrate both post-transcriptional regulation of Hmgn2 by miR-23a/b and post-translational regulation of gene expression by Hmgn2-transcription factor interactions. We conclude that HMGN2 regulates tooth development through its interaction with multiple transcription factors.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Transcription Factors / Transcription, Genetic / Gene Expression Regulation / Homeodomain Proteins / HMGN2 Protein / Lymphoid Enhancer-Binding Factor 1 / Amelogenesis Limits: Animals Language: En Journal: J Biol Chem Year: 2022 Document type: Article Affiliation country: United States Publication country: EEUU / ESTADOS UNIDOS / ESTADOS UNIDOS DA AMERICA / EUA / UNITED STATES / UNITED STATES OF AMERICA / US / USA

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Transcription Factors / Transcription, Genetic / Gene Expression Regulation / Homeodomain Proteins / HMGN2 Protein / Lymphoid Enhancer-Binding Factor 1 / Amelogenesis Limits: Animals Language: En Journal: J Biol Chem Year: 2022 Document type: Article Affiliation country: United States Publication country: EEUU / ESTADOS UNIDOS / ESTADOS UNIDOS DA AMERICA / EUA / UNITED STATES / UNITED STATES OF AMERICA / US / USA