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Cited by 11dental development and anomaliesDevelopmental Biology and Gene RegulationBone and Dental Protein Studies

HMGN2 represses gene transcription via interaction with transcription factors Lef-1 and Pitx2 during amelogenesis

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Eliason, Steven, Su, Dan, Pinho, Flavia, Sun, Zhao, Zhang, Zichao, Li, Xiao, Sweat, Mason, Venugopalan, Shankar R. +3 more·2022·Journal of Biological Chemistry
DOI 10.1016/j.jbc.2022.102295PMC PMC9418915
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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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  • miR-23a/b are highly expressed in mature tooth germ, and they share common target genes Hmgn2 and Whsc1.

    “miR-23a/b are highly expressed in mature tooth germ, and they share common target genes, namely high mobility group protein N2 (Hmgn2), and Wolf-Hirschhorn syndrome candidate 1 gene (Whsc1).”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [118]

    The Results sections report that miR-23a and miR-23b increase at later stages of mouse tooth development and that both target and repress Hmgn2. The paper does not identify Whsc1 as a target of either miRNA, so the claim that they share both named targets is unsupported. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • The impact of miR-23 on organisms is long-lasting and can affect tooth growth during embryonic stages.

    “The studies provide evidences that the impact of miR-23 on organisms is long-lasting and can affect tooth growth during embryonic stages.”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [118]

    The Results section (Fig. 6C; page unavailable) examines embryonic mouse mandibles and links increasing miR-23a/b expression with changes associated with tooth development. The Discussion says miR-23 permits dental epithelial differentiation, but the paper does not establish a long-lasting effect on organisms or directly demonstrate altered embryonic tooth growth. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Expression of miR-23 in mouse embryos leads to a decrease in Hmgn2, which subsequently boosts amelogenin expression through multiple transcription factors including Pitx2, Dlx2, Lef-1, and FoxJ1.

    “The expression of miR-23 in mouse embryos leads to a decrease in Hmgn2, which subsequently boosts the amelogenin expression through multiple transcription factors, including Pitx2, Dlx2, Lef-1, and FoxJ1 [118,119].”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [118]

    The Results section on miR-23a+b reports that miR-23 represses Hmgn2 and increases amelogenin in dental epithelial cells; the paper also links HMGN2 loss to increased activity of Pitx2, Dlx2, Lef-1, and FoxJ1. In developing mouse mandibles, however, the Results report a correlation between rising miR-23 and falling Hmgn2, not a causal test of miR-23 expression in embryos. Page numbers were not available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Authors
Eliason, S., Su, D., Pinho, F., Sun, Z., Zhang, Z., Li, X., Sweat, M., Venugopalan, S. R., He, B., Bustin, M., & Amendt, B. A.
Affiliations
  • University of Iowa (US)
  • Janssen Research & Development (United States) (US)
  • Washington University in St. Louis (US)
  • Boston Children's Hospital (US)
  • National Institutes of Health (US)
Corresponding author
Amendt, Brad A.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2022-09
Volume
298
Issue
9
Pages
102295
ISSN
0021-9258 (ISSN-L)
DOI
10.1016/j.jbc.2022.102295
PMC
PMC9418915
OpenAlex
W4286511750
Cited by
11
References
0
Citations by year
2026: 3 · 2025: 2 · 2024: 3 · 2023: 3
FWCI
0.65
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (DE028527, DE13941)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › dental development and anomalies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Health Sciences › Medicine › Rheumatology › Bone and Dental Protein Studies
Keywords
HMGN2, transcriptional repression, LEF1, PITX2, Dlx2, Foxj1, amelogenesis, tooth development, HMG-box domain, H3K4me2, open chromatin, microRNA-23a, amelogenin, craniofacial development
MeSH terms
Homeobox Protein PITX2, Amelogenesis, Animals, Chromatin, Gene Expression Regulation, Transcription Factors, Transcription, Genetic, Homeodomain Proteins, HMGN2 Protein, MicroRNAs, Mice, Lymphoid Enhancer-Binding Factor 1, Amelogenin

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