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

## TL;DR

This study shows that the enzyme SETD2 is crucial for tooth dentin formation by regulating specific genes and signaling pathways in mice.

## Contribution

The study reveals a novel role of SETD2-mediated H3K36me3 in regulating Col11a2 and Sema3e for dentinogenesis.

## Key findings

- SETD2 is essential for odontoblast differentiation and dentin formation in mice.
- SETD2 regulates H3K36me3 at the loci of Col11a2 and Sema3e, affecting their transcription.
- COL11A2 and SEMA3E promote odontoblast differentiation via AKT1 signaling.

## 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.

Summary: Setd2 deprivation in odontoblasts reduces both H3K36me3 occupancy at the loci of Sema3e and Col11a2 and transcription of these two genes, leading to impaired AKT1 activation and dentin developmental defects.