A novel functional interaction between a chromatin remodeler and cohesin in neuronal activity-induced enhancer architecture

神经元活动诱导的增强子结构中染色质重塑剂和粘连蛋白之间的新型功能相互作用

• 批准号: 10537687
• 负责人: Jiang Wu
• 金额: $ 45.1万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10537687
• 关键词: ATP Hydrolysis; ATP phosphohydrolase; Affect; Architecture; Binding; Brain; Brain Diseases; Chromatin; Chromatin Remodeling Factor; Chromosome Structures; Complex; DNA Binding; DNA Sequence Alteration; Disease; Enhancers; Environment; Event; Foundations; Future; G1 Phase; Gene Activation; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Germ Lines; Hela Cells; Histones; Homeostasis; Human; Impairment; Knockout Mice; Link; Mediating; Mental disorders; Methods; Molecular Genetics; Mutant Strains Mice; Mutation; Neurons; PRC1 Protein; Pathology; Pathway interactions; Phosphorylation; Play; Proteins; Reporting; Role; SMARCA4 gene; Solid; Stimulus; Structure; Symptoms; Techniques; chromatin remodeling; cohesin; conditional knockout; developmental disease; epigenetic regulation; genome-wide; improved mobility; long term memory; neurodevelopment; novel; promoter; relating to nervous system; release factor; response; tool

Summary: Genome architecture, especially cohesin-mediated enhancer-promoter (E-P) looping, is a critical step for enhancer activation and gene transcription. It remains largely unknown how chromatin regulators, which often function locally at enhancers and promoters, affect long range E-P looping. BAF chromatin remodeling complexes regulate transcription using energy derived from ATP hydrolysis to modulate chromatin accessibilities and the local chromatin environment. Cohesin complexes form a ring-like structure to mediate chromosome organization, including E-P looping, during the G0/G1 phase. Genetic mutations in both BAF and cohesin subunits are associated with neural developmental disorders, which share similarities in symptoms. Activity- regulated gene (ARG) expression plays an essential role in short-term neural responses as well as in long-term memory formation, homeostasis, and adaptation. In response to neuronal activation, cohesin-mediated E-P interactions either form de novo or become strengthened, a critical step in enhancer activation and ARG expression. However, it remains unclear how neuronal activities promote cohesin function in enhancer activation. Recently, we reported that BRG1, a core ATPase subunit in BAF complexes, plays a central role in regulating enhancer activities, and we identified a phosphorylation event that fine-tunes BRG1 function in response to neuronal stimulation. We showed that BRG1 deletion as well as BRG1 phospho-mutations led to impaired enhancer activation and E-P looping in response to neuronal activities. It remains unclear how locally functioning chromatin remodelers regulate cohesin binding and long-range E-P looping. A recently revealed important mechanism regulating cohesin binding to enhancers is the binding mobility of cohesin to chromatin. The cohesin release factor WAPL maintains a pool of dynamic cohesin, which is required for cohesin binding to enhancers and the expression of lineage-specific genes. We performed preliminary studies in HeLa cells and in primary neurons and observed that BRG1 had a similar function in regulating cohesin dynamics and in regulating the global distribution of cohesin on chromatin. BRG1 deletion led to a global increase in cohesin binding to chromatin but a paradoxical decrease in its binding to specific enhancers and promoters. BRG1 enhanced WAPL function in cohesin release, and BRG1 deletion impaired cohesin dynamics. Since the BAF complex can use the energy derived from ATP hydrolysis to improve the mobility of not only DNA bound histones, but also other proteins including itself and the PRC1 complex, it could also mobilize chromatin-bound cohesin. We hypothesize that BRG1 and its phosphorylation could promote neuronal activity-induced cohesin dynamics, cohesin global redistribution on chromatin, and cohesin-mediated E-P looping. Using BRG1 and cohesin mutant mice and novel genome-wide techniques, we will study how BRG1 regulates cohesin chromatin distribution and how cohesin regulates BRG1-dependent neuronal ARG activation. We will determine the important functions of chromatin remodeling factors and genome architecture regulators in neuronal gene activation and brain disorders.

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