Epigenetic regulatory roles of Mll4 in palate development

Mll4 在上颚发育中的表观遗传调控作用

基本信息

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
项目类别：
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

项目摘要

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..

项目摘要每年在美国，有2500多名婴儿出生时出生的口感（CP）。 CP是由胚胎发育过程中古质发生的破坏。该建议旨在描述关键分子古质发生的途径，这将导致开发更好的诊断，治疗和预防与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，可创建转录活性开放染色质标记。与其他亚基，例如UTX（又称KDM6A），MLL4形成复合物（MLL4-C），它是触发细胞类型特异性目标的重要“表观遗传”转录共激活因子基因表达。 MLL4基因以及UTX基因的突变引起人类发育疾病kabuki综合征（KS），其特征是颅面异常，包括CP。我们发现有条件敲除（CKO）小鼠具有MLL4的特异性缺失（NCC）开发各种KS样颅面表型，包括CP的100％渗透率。这些结果表明 MLL4在发育中发育的palatal间充质中的细胞自主作用的丧失导致CP和 KS的其他颅面结构缺陷。这，我们假设MLL4-C依赖性的失调基因调节程序导致发育和细胞定义在口感发育期间，导致在MLL4-CKO小鼠和人类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，表征MLL4缺陷小鼠中left裂缺陷的表型；目标2，通过 MLL4-C调节古质发生。基于我们从独特的鼠标模型中的强大初步数据建立开发具有100％外渗的CP，该提案将大大提高我们对古质发生的理解和 CP发病机理..