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: 10289139
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10289139
• 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; craniofacial structure; 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..

项目摘要 在美国，每年有超过2,500名婴儿出生时患有腭裂（CP）。CP是由 在胚胎发育过程中腭发生的中断。该建议旨在描述关键的分子 腭发育的途径，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。 MLL 4（aka KMT 2D）是组蛋白H3-赖氨酸4甲基转移酶，其产生转录活性的开放式结构。 染色质标记。MLL 4与其他亚基，如UTX（又名KDM 6A）一起形成复合物（MLL 4-C）， 其作为一种重要的“表观遗传”转录辅激活因子， 基因表达。MLL 4基因以及UTX基因的突变导致人类发育异常。 疾病歌舞伎综合征（KS），其特征在于颅面异常，包括CP。 我们发现，M114神经嵴细胞（NCC）特异性缺失的条件性敲除（cKO）小鼠， 发展各种KS样颅面表型，包括100%的CP检出率。这些结果表明 MLL 4在发育中的腭间充质中的细胞自主作用的丧失导致CP， KS的其他颅面结构缺陷。因此，我们假设MLL 4-C依赖性细胞因子的调节异常， 基因调控程序导致腭发育过程中的发育和细胞缺陷， 在M114-cKO小鼠和人KS中观察到CP。为了检验我们的假设，我们将追求两个具体目标：目标1， 目的2：通过M114基因缺陷小鼠的腭裂模型，研究M114基因缺陷小鼠腭裂的发生机制。 M114-C调控腭发育。基于我们从一个独特的小鼠模型获得的强大的初步数据， 发展CP与100%的转化率，这一建议将大大推进我们对腭发育的理解， CP发病机制