Chromatin Accessibility Predetermines Odontoblast Terminal Differentiation

Abstract

Embryonic development and stem cell differentiation are orchestrated by changes in sequential binding of regulatory transcriptional factors to their motifs. These processes are invariably accompanied by the alternations in chromatin accessibility, conformation, and histone modification. Odontoblast lineage originates from cranial neural crest cells and is crucial in dentinogenesis. Our previous work revealed several transcription factors (TFs) that promote odontoblast differentiation. However, it remains elusive as to whether chromatin accessibility affects odontoblast terminal differentiation. Herein, integration of single-cell RNA-seq and bulk RNA-seq revealed that in vitro odontoblast differentiation using dental papilla cells at E18.5 was comparable to the crown odontoblast differentiation trajectory of OC (osteocalcin)-positive odontogenic lineage. Before in vitro odontoblast differentiation, ATAC-seq and H3K27Ac CUT and Tag experiments demonstrated high accessibility of chromatin regions adjacent to genes associated with odontogenic potential. However, following odontoblastic induction, regions near mineralization-related genes became accessible. Integration of RNA-seq and ATAC-seq results further revealed that the expression levels of these genes were correlated with the accessibility of nearby chromatin. Time-course ATAC-seq experiments further demonstrated that odontoblast terminal differentiation was correlated with the occupation of the basic region/leucine zipper motif (bZIP) TF family, whereby we validated the positive role of ATF5 in vitro. Collectively, this study reports a global mapping of open chromatin regulatory elements during dentinogenesis and illustrates how these regions are regulated via dynamic binding of different TF families, resulting in odontoblast terminal differentiation. The findings also shed light on understanding the genetic regulation of dentin regeneration using dental mesenchymal stem cells.

Xbp1 promotes odontoblastic differentiation through modulating mitochondrial homeostasis

“…Transcriptional regulatory network centered on TFs has been extensively involved in cell fate determination during tooth development 3 . Our study showed that XBP1 was expressed during odontoblastic differentiation and functioned as an active TF, similar to other bZIP family members such as ATF2, ATF5, and ATF6 4–6 . The alterations in chromatin accessibility and transcriptome atlas caused by Xbp1 knockdown indicated that the odontoblastic differentiation process and the mitochondrial biological activity were disturbed.…”

“…3 Our study showed that XBP1 was expressed during odontoblastic differentiation and functioned as an active TF, similar to other bZIP family members such as ATF2, ATF5, and ATF6. [4][5][6] The alterations in chromatin accessibility and transcriptome atlas caused by Xbp1 knockdown indicated that the odontoblastic differentiation process and the mitochondrial biological activity were disturbed. Mitochondrial quality control regulation was of great importance in the lifetime of organisms, including development and aging.…”

YAP1 Recognizes Inflammatory and Mechanical Cues to Exacerbate Benign Prostatic Hyperplasia via Promoting Cell Survival and Fibrosis

“…[ 28 ] What else, stromal cells have the potential to differentiate into easily‐contractile α‐SMA‐positive myofibroblasts, which are prone to secrete high amounts of ECM proteins such as collagen I/III, ultimately resulting in the replacement of normal tissue by stiff and low‐compliant fibrotic tissue. [ 22b,29 ] We found that the inhibition of YAP1 reversed LPS‐induced EMT switch of BPH‐1 cells and ECM proteins synthesis of WPMY‐1 cells. These findings indicated that targeting YAP1 could suppress cell growth and fibrosis, achieved by inhibiting proliferation, accelerating apoptosis, reversing EMT and decreasing ECM production, thereby preventing BPH progression.…”

Single-Cell Transcriptome Analysis Defines Expression of Kabuki Syndrome-Associated KMT2D Targets and Interacting Partners

“…The dental pulp-derived MSCs exhibit multipotent differentiation capacity and are considered a promising stem cell source for tissue engineering and regenerative medicine [45]. Over the past decades, a growing body of scientific evidence shows that epigenetic mechanisms play a major role in lineage specification and gene regulatory networks underlying MSC differentiation [46][47][48]. Therefore, further research toward identifying the molecular pathways through which KMT2D controls gene expression in dental pulp stem…”