Epigenetic regulatory roles of Mll4 in palate development

Mll4 在上颚发育中的表观遗传调控作用

• 批准号: 10459544
• 负责人: Hyuk Jae Edward Kwon
• 金额: $ 15.95万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459544
• 关键词: Acetyltransferase; Address; Adhesions; Binding; Biochemical Genetics; Bioinformatics; Breathing; Cell Survival; Cell physiology; Cells; ChIP-seq; Child; Chromatin; Cleft Palate; Complex; Craniofacial Abnormalities; Data; Data Set; Defect; Dental; Dental Care; Development; Developmental Process; Diagnosis; Eating; Embryo; Embryonic Development; Epigenetic Process; Etiology; Family; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genotype; Health; Hearing; Histone Deacetylase Inhibitor; Histone H3; Human; Impairment; Kabuki Make-Up Syndrome; Knockout Mice; Knowledge; Lysine; Mesenchymal; Mesenchyme; Methods; Methyltransferase; Molecular; Mus; Mutation; Neural Crest Cell; Operative Surgical Procedures; Osteogenesis; Outcome; Palate; Pathogenesis; Pathway interactions; Patients; Penetrance; Phenotype; Play; Positioning Attribute; Prevention; Process; Property; Quality of life; Regulator Genes; Reporting; Research; Role; Signal Pathway; Speech Therapy; Structural defect; Testing; Time; Tissues; Transcription Coactivator; United States; causal variant; cell motility; cell type; conditional knockout; craniofacial; craniofacial disorder; design; developmental disease; experience; genome-wide; improved; mouse model; palatal shelves; palatogenesis; programs; recruit; repaired; socioeconomics; transcription factor; transcriptome sequencing

PROJECT SUMMARY Each year in the United States, more than 2,500 babies are born with a cleft palate (CP). CP is caused by disruption of palatogenesis during embryonic development. This proposal aims to delineate critical molecular pathways of palatogenesis, which will lead to development of better methods for diagnosis, treatment and prevention of issues associated with CP. MLL4 (aka KMT2D) is a histone H3-lysine 4 methyltransferase that creates transcriptionally active open chromatin marks. Together with other subunits, such as UTX (aka KDM6A), MLL4 forms a complex (MLL4-C), which functions as an important “epigenetic” transcriptional coactivator that triggers cell type-specific target gene expression. Mutations in the MLL4 gene, as well as the UTX gene, cause the human developmental disorder Kabuki syndrome (KS), which is characterized by craniofacial abnormalities, including CP. We discovered that conditional knockout (cKO) mice with neural crest cell (NCC)-specific deletion of Mll4 develop various KS-like craniofacial phenotypes, including 100% penetrance for CP. These results suggest that the loss of cell autonomous actions of MLL4 in the developing palatal mesenchyme results in CP and other craniofacial structural defects of KS. Thus, we hypothesize that dysregulation of the MLL4-C-dependent gene regulatory program leads to developmental and cellular deficits during palate development, resulting in CP observed in Mll4-cKO mice and human KS. To test our hypothesis, we will pursue two specific aims: Aim 1, to characterize the phenotype of cleft palate defect in Mll4-deficient mice; Aim 2, to define the mechanisms by which Mll4-C regulates palatogenesis. Building on our strong preliminary data from a unique mouse model that develops CP with 100% penetrance, this proposal will greatly advance our understanding of palatogenesis and CP pathogenesis..

项目总结 在美国，每年有超过2500名婴儿出生时患有腭裂(CP)。CP是由以下原因引起的 胚胎发育过程中腭部发育的中断。这项提案旨在描绘关键分子 腭裂发生的途径，这将导致更好的诊断、治疗和治疗方法的发展 预防与CP相关的问题。 MLL4(又名KMT2D)是一种组蛋白H3-赖氨酸4甲基转移酶，能产生转录活性的Open 染色质痕迹。MLL4与其他亚基如UTX(又名KDM6A)一起形成络合物(MLL4-C)， 它是一个重要的“表观遗传”转录辅助激活因子，可触发特定细胞类型的靶标 基因表达。MLL4基因和UTX基因的突变导致人类发育 无序性歌舞伎综合征(KS)，以头面部异常为特征，包括CP。 我们发现，条件基因敲除(CKO)小鼠具有神经脊细胞(NCC)特异性的MLL4缺失 形成各种KS样头面部表型，包括100%的CP外显率。这些结果表明 在发育中的腭间充质中MLL4的细胞自主作用的丧失导致CP和 KS的其他头面部结构缺陷。因此，我们假设MLL4-C依赖的调节失调 基因调控程序导致腭部发育过程中的发育和细胞缺陷，导致 在MLL4-CKO小鼠和人KS中观察到CP。为了验证我们的假设，我们将追求两个具体目标：目标1， 鉴定MLL4基因缺陷小鼠的腭裂表型；目的2，通过以下方法确定其机制 其中MLL4-C调控着腭裂的发生。建立在我们来自独特的老鼠模型的强大初步数据的基础上 这一建议将极大地促进我们对腭裂发生和发展的了解 CP病机..