CREB3L1 deficiency impairs odontoblastic differentiation and molar dentin deposition partially through the TMEM30B.

IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE
Yuanyuan Li, Yuxiu Lin, Jinqiang Guo, Delan Huang, Huanyan Zuo, Hanshu Zhang, Guohua Yuan, Huan Liu, Zhi Chen
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Abstract

Odontoblasts are primarily responsible for synthesizing and secreting extracellular matrix proteins, which are crucial for dentinogenesis. Our previous single-cell profile and RNAscope for odontoblast lineage revealed that cyclic adenosine monophosphate responsive element-binding protein 3 like 1 (Creb3l1) was specifically enriched in the terminal differentiated odontoblasts. In this study, deletion of Creb3l1 in the Wnt1+ lineage led to insufficient root elongation and dentin deposition. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and RNA sequencing were performed to revealed that in CREB3L1-deficient mouse dental papilla cells (mDPCs), the genes near the closed chromatin regions were mainly associated with mesenchymal development and the downregulated genes were primarily related to biological processes including cell differentiation, protein biosynthesis and transport, all of which were evidenced by a diminished ability of odontoblastic differentiation, a significant reduction in intracellular proteins, and an even greater decline in extracellular supernatant proteins. Dentin matrix protein 1 (Dmp1), dentin sialophosphoprotein (Dspp), and transmembrane protein 30B (Tmem30b) were identified as direct transcriptional regulatory targets. TMEM30B was intensively expressed in the differentiated odontoblasts, and exhibited a significant decline in both CREB3L1-deficient odontoblasts in vivo and in vitro. Deletion of Tmem30b impaired the ability of odontoblastic differentiation, protein synthesis, and protein secretion in mDPCs. Moreover, overexpressing TMEM30B in CREB3L1-deficient mDPCs partially rescued the extracellular proteins secretion. Collectively, our findings suggest that CREB3L1 participates in dentinogenesis and facilitates odontoblastic differentiation by directly enhancing the transcription of Dmp1, Dspp, and other differentiation-related genes and indirectly promoting protein secretion partially via TMEM30B.

Abstract Image

CREB3L1 缺乏会部分通过 TMEM30B 影响牙本质分化和磨牙牙本质沉积。
牙本质母细胞主要负责合成和分泌细胞外基质蛋白,这对牙本质的形成至关重要。我们之前对骨母细胞系的单细胞图谱和 RNAscope 发现,环腺苷酸单磷酸反应元件结合蛋白 3 like 1(Creb3l1)特异性地富集在末端分化的骨母细胞中。在这项研究中,在 Wnt1+ 系中缺失 Creb3l1 会导致牙根伸长和牙本质沉积不足。通过高通量测序(ATAC-seq)和RNA测序对转座酶可进入染色质进行检测,发现在CREB3L1缺失的小鼠牙乳头细胞(mDPCs)中,封闭染色质区域附近的基因主要与间质发育有关,而下调的基因主要与细胞分化等生物过程有关、蛋白质的生物合成和运输,所有这些都表现为牙本质分化能力的减弱、细胞内蛋白质的显著减少以及细胞外上清液蛋白质的更大幅度下降。牙本质基质蛋白 1(Dmp1)、牙本质糖磷蛋白(Dspp)和跨膜蛋白 30B(Tmem30b)被确定为直接转录调控靶标。TMEM30B在分化的颌骨细胞中大量表达,在体内和体外CREB3L1缺陷的颌骨细胞中均表现出显著下降。缺失 Tmem30b 会损害 mDPCs 中骨母细胞的分化能力、蛋白质合成能力和蛋白质分泌能力。此外,在 CREB3L1 缺失的 mDPCs 中过表达 TMEM30B 可部分修复细胞外蛋白的分泌。总之,我们的研究结果表明,CREB3L1 通过直接增强 Dmp1、Dspp 和其他分化相关基因的转录,并部分通过 TMEM30B 间接促进蛋白质分泌,从而参与牙本质生成并促进牙本质分化。
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来源期刊
International Journal of Oral Science
International Journal of Oral Science DENTISTRY, ORAL SURGERY & MEDICINE-
CiteScore
31.80
自引率
1.30%
发文量
53
审稿时长
>12 weeks
期刊介绍: The International Journal of Oral Science covers various aspects of oral science and interdisciplinary fields, encompassing basic, applied, and clinical research. Topics include, but are not limited to: Oral microbiology Oral and maxillofacial oncology Cariology Oral inflammation and infection Dental stem cells and regenerative medicine Craniofacial surgery Dental material Oral biomechanics Oral, dental, and maxillofacial genetic and developmental diseases Craniofacial bone research Craniofacial-related biomaterials Temporomandibular joint disorder and osteoarthritis The journal publishes peer-reviewed Articles presenting new research results and Review Articles offering concise summaries of specific areas in oral science.
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