2. Academic Validation
  3. H3K36me3 modification by SETD2 is essential for Col11a2 and Sema3e transcription to maintain dentinogenesis in mice

H3K36me3 modification by SETD2 is essential for Col11a2 and Sema3e transcription to maintain dentinogenesis in mice

  • Development. 2025 Jul 15;152(14):dev204352. doi: 10.1242/dev.204352.
Jiaxin Niu 1 2 3,  Jing Fu 1 2 3 4,  Hao Feng 1 2 3,  Jiahao Han 1,  Zhi Chen 1,  Guobin Yang 1,  Guohua Yuan 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
  • 2 Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China.
  • 3 Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China.
  • 4 Pediatric Dentistry, Nanjing Stomatology Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing 210008, China.
PMID: 40554768 DOI: 10.1242/dev.204352
Abstract

Dentin is a major mineralized component of teeth generated by odontoblasts. Several types of histone methylation have been reported to play important roles in odontoblast differentiation and dentinogenesis. However, the role of methylation on histone 3 at lysine 36 (H3K36) remains enigmatic. Here, we demonstrate high expression of SETD2, a methyltransferase catalyzing the trimethylation of H3K36 (H3K36me3), in the odontoblast layer. In vitro knockdown experiments and in vivo observations of two conditional knockout mouse models reveal that SETD2 is essential for odontoblast differentiation and dentinogenesis. Integrated analyses of RNA Sequencing and spike-in CUT&Tag Sequencing data show that SETD2 is crucial for both H3K36me3 occupancy at the loci of Col11a2 and Sema3e and their transcription. Further experiments verify that COL11A2 and SEMA3E act upstream of Akt1 signaling, promoting odontoblastic differentiation. In vitro and in vivo activation of Akt1 using SC79 (an Akt Activator) partially rescues the impaired odontoblast differentiation caused by Setd2 knockdown or deficiency. Therefore, our findings indicate that H3K36me3 mediated by SETD2 is essential for dentinogenesis by regulating the expression of Col11a2 and Sema3e and Akt1 signaling.

Keywords

Dentinogenesis; Histone methylation; Odontoblast differentiation; SET domain containing 2; Trimethylation of histone H3 at lysine 36.

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