Role of miRNA from amelogenin exon4 in enamel formation

釉原蛋白外显子 4 的 miRNA 在牙釉质形成中的作用

• 批准号: 10427352
• 负责人: Yukiko Nakano
• 金额: $ 37.97万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10427352
• 关键词: Affect; Alternative Splicing; Ameloblasts; Amelogenesis Imperfecta; Animal Model; Binding; Biological Assay; CXCL11 gene; CYP27B1 gene; Cells; Data; Defect; Dental Enamel; Development; Disease; Electrophoretic Mobility Shift Assay; Enamel Formation; Enamel Organ; Enhancers; Esthetics; Etiology; Event; Exons; Foundations; Future; Genes; Genetic; Goals; Growth; Human; Hypersensitivity; In Vitro; Infection; Inherited; Knockout Mice; Knowledge; LAMC2 gene; Link; Messenger RNA; MicroRNAs; Molecular; Mus; Mutate; Mutation; NFIA gene; Organ; Outcome Study; Pathologic; Patients; Phenotype; Play; Preparation; Process; Production; Proteins; Publishing; Quality of life; RNA; RNA Splicing; Reporter; Role; SRSF2 gene; Signal Transduction; Syndrome; TSC1 gene; Testing; Therapeutic; Tissues; Tooth structure; Validation; Variant; amelogenin; gain of function; improved; in silico; in vivo; individualized medicine; leucine-rich amelogenin peptide; loss of function; mechanical properties; novel; precision medicine; skeletal

Project Summary/Abstract Genetics of enamel formation is not well studied yet. In humans, hereditary enamel defects (HED) occurs as a non-syndromic enamel conditions (amelogenesis imperfecta/AI) or syndromic conditions affecting tissues or organs in addition to the enamel phenotype. At least 73 genes are known to involve in HED. Amelogenin gene is the most essential one of those genes, and causes X-linked AI when mutated. Amelogenin gene is processed via alternative splicing to produce the two major mRNAs for proteins with distinct functions. During these events, exon4 is always spliced out, and the importance of the spliced-out exon4 has not been well studied. We recently published that a novel microRNA (miRNA) is derived from the spliced-out exon4 (miR-exon4). This miR-exon4 regulates expression of Runx2 in ameloblasts. In tooth, Runx2 is known associate with HED, thus the critical role of miR-exon4 for enamel formation is suggested. miRNAs play important roles in tooth formation. Nevertheless, clear links between the miRNAs, tooth development and diseases have yet to be established. Particularly, how miR-exon4 is involved in normal and pathologic enamel formation is not clear. Enamel is an indispensable tissue layer of the tooth, since defective enamel severely affects the quality of life for HED patients by causing poor aesthetics, hypersensitive tooth, reduced mechanical property and occlusion. Hence, there is an urgent necessity to increase our knowledge of this newly discovered miR-exon4 associated with enamel formation. Our long-term goal is to thoroughly understand how molecular signaling directs enamel formation, particularly the involvement of molecules derived from amelogenin gene. Our overall objective for this proposal is to discover how miR-exon4 formation is initiated and how it contributes to enamel formation. In our published and preliminary studies, we found that miR-exon4 regulates HED-causative genes including Runx2. Our in silico analysis demonstrated that most of the amelogenin mutations causing X-linked AI disrupt alternative splicing, which will affect production of miR-exon4. Taken together, our central hypothesis is that production of miR-exon4 is initiated via alternative splicing, and miR-exon4 regulates molecules involved in HED. This hypothesis will be tested with the following specific aims; 1) Determine how alternative splicing of exon4 is regulated to initiate miR- exon4 formation, 2) Reveal the mechanism by which miR-exon4 regulates Runx2 expression during enamel formation, and 3) Understand how miR-exon4 plays important roles in enamel formation in vivo. These knowledge will advance our understanding of molecular mechanisms regulating enamel formation, in particular, the mechanisms associated with the etiology of X-linked AI. Our findings will provide useful knowledge foundation to develop the strategies in the precision medicine to customize the treatment for X-linked AI. Moreover, as the role of miR-exon4 will be further clarified and established, miR-exon4 will potentially be used as a therapeutic molecule to improve the quality of the enamel in the future.

项目总结/文摘

项目成果

An miRNA derived from amelogenin exon4 regulates expression of transcription factor Runx2 by directly targeting upstream activators Nfia and Prkch.

• DOI: 10.1016/j.jbc.2022.101807
• 发表时间: 2022-05
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Shemirani, Rozana;Lin, Gan;Uyghurturk, Dawud Abduweli;Le, Michael;Nakano, Yukiko
• 通讯作者: Nakano, Yukiko

Mutations Causing X-Linked Amelogenesis Imperfecta Alter miRNA Formation from Amelogenin Exon4.

• DOI: 10.1177/00220345231180572
• 发表时间: 2023-10
• 期刊: Journal of dental research
• 影响因子: 7.6