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Deciphering the Molecular Orchestrators of Heterochromatin-Lamina Interactions at the Nuclear Periphery

破译核外围异染色质-层相互作用的分子协调者

基本信息

批准号：
10641656
负责人：
Ashley Karnay
金额：
$ 4.77万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641656
关键词：
3-Dimensional Adopted Cardiac Cardiac Myocytes Cardiomyopathies Cell Nucleus Cells Cessation of life Chromatin Chromosomes Complex Coupled Coupling Degenerative Disorder Development Developmental Process Disease Embryonic Development Epigenetic Process Etiology Fibrosis Foundations Fragile X Syndrome Frequencies Friedreich Ataxia Functional disorder Gene Expression Gene Order Gene Silencing Genes Genetic Genetic Transcription Genome Genomic Segment Genomics Health Heart Hypertrophy Heterochromatin Histone H3 Human Development Imaging technology Link Lysine Maintenance Mammalian Cell Manuscripts Mediating Mediator Mentors Microscopy Modification Molecular Neurodegenerative Disorders Neurodevelopmental Disorder Nuclear Nuclear Lamina Organogenesis Pathologic Pathology Peripheral Plasmids Play Population Positioning Attribute Process Proteins Radial Regulatory Element Research Research Personnel Role Specificity Testing Work cell type experimental study gene repression genetic element genetic regulatory protein genome-wide genomic locus human disease insight mammalian genome overexpression population based post-doctoral training programs segregation skills training opportunity

项目摘要

Deciphering the Molecular Orchestrators of Heterochromatin-Lamina Interactions at the Nuclear Periphery. Ashley M Karnay Abstract It is well established that the eukaryotic genome is segregated within three dimensional nuclear space, with specific genomic regions adopting subnuclear positions relative to specific nuclear landmarks. One such nuclear landmark associated is the nuclear lamina (NL) at the nuclear periphery. Positioning of specific genes at the NL correlates with enrichment in heterochromatin-associated epigenetic signatures, such as dimethylation of Lysine 9 on Histone H3 (H3K9me2), and repression of gene transcription. The dynamic coupling of peripheral positioning and gene silencing plays a key role in directing crucial developmental processes such as cardiomyocyte lineage restriction and goes awry in genetic forms of cardiomyopathy and other diseases. Genomic regions that make contact with the NL are defined as lamina-associated domains (LADs). Distributed across all chromosomes, these large domains dynamically interact with the NL to release or attach genes and regulatory elements in accordance with cell-type and differentiation state-specific gene expression programs. Specifically, loss of LADs results in precocious cardiac differentiation. How chromatin-lamina interactions are established and maintained remains poorly understood. Endogenously-encoded sequences sufficient for peripheral targeting of LADs have not been identified, strongly supporting the existence of regulatory proteins, epigenetic modifications or biomolecular processes capable of mediating chromatin-NL contacts. However, the precise orchestrators of spatial and temporal dynamics between LADs and the nuclear periphery remain elusive. By combining targeted manipulations of local transcriptional states and epigenetic signatures with single-cell microscopy and population-based genomics analysis I will test the hypothesis that the heterochromatin- associated epigenetic mark H3K9me2 is required to maintain sequestered genomic loci at the nuclear periphery while transcriptional repression serves to establish chromatin-lamina interactions. These studies will provide mechanistic insights into how chromatin states and gene activity are coupled to gene radial positioning. By probing peripheral chromatin organizational principles at the single-cell level while simultaneously analyzing higher-order genome organization at the population level, I can uniquely dissect the underlying mechanism mediating the spatial organization of the genome. Elucidating the link between nuclear organization, human development and disease etiology is crucial to understanding how these relationships impact organogenesis and disease.

解读核中异染色质-层间相互作用的分子协调者