Uncovering the function of histone variant H2BE in neurons

揭示组蛋白变体 H2BE 在神经元中的功能

基本信息

批准号：
10462825
负责人：
Emily Ruth Feierman Hyatt
金额：
$ 4.68万
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：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10462825
关键词：
ATAC-seq Address Affect Animal Behavior Antibodies Atomic Force Microscopy Behavior Behavioral Binding Biochemical Biology Brain Brain region Brain-Derived Neurotrophic Factor Cell physiology Cells ChIP-seq Chromatin Chromatin Fiber Chromatin Structure Cognition Cognitive Complex DNA Packaging Data Data Set Environment Epigenetic Process Exposure to Gene Expression Gene Expression Profile Gene Expression Regulation Genes Genetic Transcription Genome Genomic Segment Genomics Goals Heterochromatin Histone H1 Histones Immediate-Early Genes Knock-out Knockout Mice Learning Link Longevity Mass Spectrum Analysis Memory Memory Disorders Mitotic Molecular Mus Neurons Nucleosomes Olfactory Epithelium Olfactory Pathways Output Pathway interactions Phenotype Post-Translational Protein Processing Proteins Regulation Research Role Short-Term Memory Signal Transduction Stimulus Synapses Techniques Testing Therapeutic Tissues Transcriptional Regulation Translating Treatment Factor Variant Work XCL1 gene base behavior influence behavior test behavioral response behavioral study design environmental enrichment for laboratory animals epigenetic regulation extracellular fear memory flexibility gene repression genome-wide insight interest long term memory mouse model nervous system disorder novel response transcriptome sequencing whole genome

项目摘要

Project Summary The goal of this proposal is to elucidate the molecular and behavioral function of histone variant H2BE in neurons. Histone variants, which are encoded by separate genes, can substitute for the canonical histone proteins (H2A, H2B, H3, and H4) and are involved in regulation of many cellular processes and gene expression. The histone variant H2BE was discovered in the mouse main olfactory epithelium, where it affects olfactory neuron function and longevity. While H2BE was previously thought to be exclusively expressed in the olfactory system, our lab developed a highly specific antibody against H2BE and demonstrated that H2BE is present throughout the brain. However, despite the importance of histone variants in controlling neuronal function, to date, H2BE remains unstudied outside of the olfactory system. Here, I propose to determine how H2BE alters chromatin structure, neuronal gene expression, and animal behavior. I hypothesize that H2BE decreases binding of linker histone H1, controls expression of activity-dependent genes, and is necessary for cognitive flexibility, spatial learning, and fear memory. To test my hypothesis, I will combine genome-wide sequencing, mouse models, and animal behavior with molecular and biochemical techniques from the chromatin biology field. In Aim 1, I will determine how H2BE expression alters chromatin structure. I will use ChIP-sequencing to define the genomic localization of H2BE at baseline and in response to external signals. My preliminary data demonstrates that H2BE promotes an open chromatin configuration and decreases binding of heterochromatin-associated proteins. Therefore, I will examine how H2BE affects the composition of the chromatin fiber. Specifically, I will use ChIP-seq to determine how H2BE incorporation affects localization of linker histone H1. Aim 2 addresses the role of H2BE in neuronal gene expression and mouse behavior. First, I will test the effects of H2BE knockout on RNA-sequencing of neurons with and without external stimulation. Second, I will perform a battery of behavioral tests using H2BE WT and KO mice designed to determine the specific brain regions most affected by H2BE loss and to fully characterize the role of H2BE in cognition. The work proposed here will reveal how histone variant H2BE contributes to the complex chromatin environment in the brain. This discovery is critical to understanding how neurons use environmental signals to control transcription and ultimately govern behavior. In developing a more complete understanding of the chromatin landscape in neurons, we will also gain insight into potential therapeutics for the treatment of the many neurological disorders that are linked to disruption of epigenetic regulation in the brain.