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Exploring novel regulatory mechanisms underlying enhancer activation and cell fate transition

探索增强子激活和细胞命运转变的新调控机制

基本信息

批准号：
10259871
负责人：
Kaixiang Cao
金额：
$ 24.09万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-08 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10259871
关键词：
3-Dimensional Animals Architecture Award Binding Binding Proteins Biochemistry Bioinformatics Biological Assay Biology Bruck-de Lange syndrome CRISPR screen Cell Differentiation process Cell Maintenance Cells Chromatin Chromatin Structure Data Deposition Development Disease Dose Down-Regulation ES Cell Line Educational workshop Embryonic Development Enhancers Ensure Environment Enzymes Epigenetic Process Equilibrium Family Gene Expression Genes Genetic Transcription Genome Genomic approach Goals Grant Hi-C Higher Order Chromatin Structure Histone H3 Human Instruction KDM1A gene Kabuki Make-Up Syndrome Knock-out Lead Leadership Lysine Malignant Neoplasms Mentors Methylation Modeling Molecular Mutation Names Output Pathogenesis Pathology Pathway interactions Phase Play Pluripotent Stem Cells Postdoctoral Fellow Process Proteomics Regulation Research Role SET Domain Stem Cell Factor Testing Thalassemia Training Transcriptional Regulation Universities Writing base cancer type career career development chromosome conformation capture clinical application course development developmental disease driver mutation embryonic stem cell experience genetic corepressor genome wide screen genome-wide graduate student high throughput screening histone methyltransferase human disease inhibitor/antagonist innovation insight loss of function loss of function mutation medical schools member new therapeutic target novel pluripotency programs protein complex recruit skills stem cell biology stem cell differentiation stem cells targeted treatment therapy development transcription factor transcriptome

项目摘要

Project Summary/Abstract Misregulation of enhancer activity leads to various developmental disorders including thalassemia, Cornelia de Lange syndrome, and Kabuki syndrome. The major enhancer regulator Mll4 belongs to the family of the Su(var)3- 9, Enhancer-of-zeste, Trithorax (SET) domain containing histone methyltransferases named COMplex of Proteins ASsociated with Set1 (COMPASS), which places methylation marks at lysine 4 of histone H3 (H3K4). Mll4 is essential for mammalian development and its heterozygous loss-of-function mutations lead to various human diseases including Kabuki syndrome and cancer. I recently demonstrated that Mll4 is the major enzyme depositing mono-methylation at H3K4 (H3K4me1), an enhancer-decorating epigenetic mark whose function remains elusive. Moreover, I have defined catalytic activity dependent and independent functions of Mll4 in enhancer modulation and stem cell differentiation, and have unveiled an antagonism between enhancer-binding epigenetic machineries in transcriptional control that could underlie the developmental consequences of the heterozygous loss-of-function mutations of Mll4 in human disease. Based on these findings, I hypothesize that Mll4 cooperates with key transcription factors and epigenetic modifiers to modulate enhancer activity, chromatin structure, and transcriptional outputs during stem cell maintenance and differentiation. The studies proposed here aim to elucidate the molecular mechanisms of enhancer regulation, and to provide insights for developing novel therapies targeting diseases driven by the loss of function of epigenetic modifiers. Specifically, the outlined research will 1) elucidate how epigenetic marks impact enhancer functions and cell fate transition; 2) determine the role of higher order chromatin structure in stem cell maintenance and differentiation; 3) identify novel factors and pathways involved in modulating enhancer activity and determining cell fate. To achieve the long-term career goal of defining the epigenetic mechanisms underlying mammalian development and disease, I will acquire training in biochemistry, proteomics, bioinformatics, stem cell biology, and genome-wide screening during the mentored phase of this application. Moreover, I will participate in grant writing workshops and career development courses to strengthen my skills in writing and leadership. With the acquired training, I will be well- prepared for the task of delineating the machineries and mechanisms in modulating gene expression, chromatin structure, and cell fate determination in the independent R00 phase. In summary, the K99/R00 award, together with the experiences that I have garnered as a graduate student and postdoc, the guidance from the mentors and collaborators, and the superb research environment at Northwestern University's Feinberg School of Medicine, will ensure a successful transition for me to continue my independent scientific career in the field of stem cell biology and epigenetics.

项目总结/文摘