Journal article
HMGN2 represses gene transcription via interaction with transcription factors Lef-1 and Pitx2 during amelogenesis
The Journal of biological chemistry, Vol.298(9), pp.1-16
09/2022
DOI: 10.1016/j.jbc.2022.102295
PMCID: PMC9418915
PMID: 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.
Details
- Title: Subtitle
- HMGN2 represses gene transcription via interaction with transcription factors Lef-1 and Pitx2 during amelogenesis
- Creators
- Steven Eliason - University of IowaDan Su - University of IowaFlavia PinhoZhao Sun - Washington University St Louis, St Louis, Missouri, USAZichao Zhang - Institute for Biosciences and Technology, Houston, Texas, USAXiao Li - Texas Heart Institute, Houston, Texas, USAMason Sweat - Boston Children's HospitalShankar R. Venugopalan - University of IowaBing He - National Institutes of HealthMichael Bustin - National Institutes of HealthBrad A. Amendt - Department of Anatomy and Cell Biology and the Craniofacial Anomalies Research Center, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.298(9), pp.1-16
- DOI
- 10.1016/j.jbc.2022.102295
- PMID
- 35872015
- PMCID
- PMC9418915
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 09/2022
- Academic Unit
- Orthodontics; Anatomy and Cell Biology; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9984288822302771
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