Abstract
Chromatin remodeling, specifically the tissue-specific regulation in mineralized tissues, is an understudied avenue of gene regulation. Here we show that Baf45a and Baf45d, two Baf45 homologs belong to ATPase-dependent SWI/SNF chromatin remodeling complex, preferentially expressed in osteoblasts and odontoblasts compared to Baf45b and Baf45c. Recently, biochemical studies revealed that BAF45A associates with Polybromo-associated BAF (PBAF) complex. However, the BAF45D subunit belongs to the polymorphic canonical BRG1-associated factor (cBAF) complex. Protein profiles of osteoblast and odontoblast differentiation uncovered a significant increase of BAF45A and PBAF subunits during early osteoblast and odontoblast maturation. Chromatin immunoprecipitation sequencing (ChIP-seq) during the bone marrow stromal cells (BMSCs) differentiation showed higher histone H3K9 and H3K27 acetylation modifications in the promoter of Baf45a and Baf45d and increased binding of bone and tooth specific transcription factor RUNX2. Overexpression of Baf45a in osteoblasts activates genes essential for the progression of osteoblast maturation and mineralization. Furthermore, shRNA-mediated knockdown of Baf45a in odontoblasts leads to markedly altered genes responsible for the proliferation, apoptosis, DNA repair, and modest decrease in dentinogenic marker gene expression. Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) assay in Baf45a knockout osteoblasts revealed a noticeable reduction in chromatin accessibility of osteoblast and odontoblast specific genes, along with transcription factor Atf4 and Klf4. Craniofacial mesenchyme-specific loss of Baf45a modestly reduced the mineralization of the tooth and mandibular bone. These findings indicated that BAF45A-dependent mineralized tissue-specific chromatin remodeling through PBAF-RUNX2 crosstalk results in transcriptional activation is critical for early differentiation and matrix maturation of mineralized tissues.
Highlights
During cellular differentiation from stem cells to progenitors to differentiated cells, must orchestrate a definite gene expression program to ensure accurate patterning and tissue specificity
bone marrow stromal cells (BMSCs) ChIP-seq analysis demonstrated that the genomic region around Baf45a and Baf45d gene promoters is active during osteogenic differentiation
The SWI/SNF chromatin remodeling complexes in mammals exist in three different forms: canonical BRM-associated factors (BAF), Polybromo BAF (PBAF), and non-canonical BAF
Summary
During cellular differentiation from stem cells to progenitors to differentiated cells, must orchestrate a definite gene expression program to ensure accurate patterning and tissue specificity. This gene expression program is fundamentally regulated largely by tissue-specific epigenetic regulation that results in spatiotemporal gene expression [1, 2]. The BRG-/BRM-associated factors (BAF) chromatin remodeling complex is an ATPase-dependent epigenetic machine with affinity to bind and slide or eject nucleosomes [3]. This process allows accessibility of lineage-specific transcriptional machinery enabling timely and appropriate control of gene expression. Further mechanistic insights demonstrated that BRD9 interacts with BRD4, which guides the recruitment of GBAF complexes to chromatin to maintain the transcriptional network of pluripotency [10]
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