Chromatin Remodeller BRD9 Orchestrates Odontoblastic Differentiation via Coordinating RUNX2-KLF4

Area of Science:

• Molecular Biology
• Developmental Biology
• Epigenetics

Background:

• Dentinogenesis requires precise odontoblast differentiation, regulated by transcription factors like RUNX2 and KLF4.
• The cofactors mediating RUNX2 and KLF4 synergy at the chromatin level during this process are largely unknown.

Purpose of the Study:

• To identify novel interactors of RUNX2 and KLF4 involved in odontoblastic differentiation.
• To elucidate the role of the chromatin remodeler BRD9 in regulating dentinogenesis.

Main Methods:

• Generation of neural crest-specific conditional knockout mice (Wnt1-Cre; Brd9^fl/fl).
• In vitro studies involving chemical BRD9 degradation.
• Integrative analyses using RNA-seq and ATAC-seq.
• Assessment of odontoblast differentiation markers (DMP1, DSPP) and FAM20C function.

Main Results:

• BRD9 was identified as a novel interactor of RUNX2 and KLF4 in odontoblasts.
• Brd9 conditional knockout mice phenocopied Runx2/Klf4 compound mutants, showing disordered odontoblasts and reduced matrix secretion.
• BRD9 loss decreased chromatin accessibility at odontogenesis-associated regions, including the Fam20c enhancer, impairing RUNX2/KLF4 binding.
• FAM20C supplementation partially rescued differentiation defects in BRD9-deficient cells.

Conclusions:

• BRD9 acts as a critical epigenetic orchestrator coordinating RUNX2-KLF4 synergy during odontoblastic differentiation.
• BRD9 regulates chromatin accessibility to facilitate the activation of key odontogenic genes, such as Fam20c.
• These findings highlight BRD9's essential role in dentinogenesis and tooth development.