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Genome-wide analysis of sex differences in cortical DNA hydroxymethylation during fear memory formation

恐惧记忆形成过程中皮质 DNA 羟甲基化的性别差异的全基因组分析

基本信息

批准号：
10041818
负责人：
MARIEKE R GILMARTIN
金额：
$ 42.58万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
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：
2020-07-20 至 2023-07-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10041818
关键词：
Address Adult Affect Alzheimer&apos s Disease Animals Anxiety Behavioral Biological Biological Markers Brain Brain Diseases Brain region Cells ChIP-seq Clustered Regularly Interspaced Short Palindromic Repeats Cognitive deficits DNA Data Development Disease Emotional Enzymes Epigenetic Process Episodic memory Extinction (Psychology)Female Fright Gene Expression Gene Targeting Generations Genes Genetic Markers Genetic Transcription Genomics Immunoprecipitation Lead Learning Link Maps Medial Mediating Memory Mental disorders Methods Methylation Modification Molecular National Institute of Mental Health Neurobiology Outcome Population Post-Traumatic Stress Disorders Pre-Clinical Model Predisposition Prefrontal Cortex Process Public Health Rattus Research Research Priority Resistance Risk Factors Role Sex Bias Sex Differences Signal Transduction Synaptic plasticity System Technology Testing Therapeutic Training Transcription Process Transcriptional Regulation Trauma Viral Woman Work chromatin immunoprecipitation classical conditioning cognitive system conditioned fear demethylation differential expression effective therapy epigenetic regulation experience experimental study fear memory genetic analysis genome wide association study genome-wide analysis innovation insight male memory consolidation men methylome methylomics next generation novel pre-clinical resilience sex sexual dimorphism transcriptomics traumatic event whole genome

项目摘要

Project Summary/Abstract Post-traumatic stress disorder (PTSD) affects nearly 8% of the population and is more prevalent in women than men. The neurobiological factors that contribute to this sex bias are largely unknown. This project addresses this gap, in accordance with NIMH Strategic Objective 1, by determining how transcriptional regulation of memory-related genes differs in males and females in support of fear memory. Recently our group demonstrated that male and female rats differentially engage signaling mechanisms within the prefrontal cortex (PFC) during the formation of a fear memory, and our preliminary findings point to sex differences in epigenetic modification of prefrontal genes. Currently, the transcriptional regulation of episodic memory within cognitive systems is poorly understood, and the impact of sex on this dynamic process is all but unknown. This represents a significant challenge to developing effective treatment for disorders such as PTSD. The objective of this proposal is to determine how DNA hydroxymethylase TET enzymes functionally regulate fear memory formation and to identify sex-specific methylomic signatures of aversive experience. DNA 5- hydroxymethylation (5-hmC), a major regulator of active (increased) transcription in cells, has been recently implicated in fear memory formation in the brain. However, whether sex differences exist in the engagement of DNA 5-hmC mechanisms during fear memory formation remain equivocal. In our preliminary studies we found that in the rat prefrontal cortex the DNA hydroxymethylase Tet2 increased in females while Tet1 decreased in males following learning in a trace fear conditioning paradigm. The central hypothesis is that TET-mediated DNA 5-hydroxymethylation of sex-specific gene targets in the prefrontal cortex facilitates the formation of fear memory. The approach uses unbiased genome-wide analysis (NIMH Strategy 1.2, Research Priority B) in combination with viral-mediated transcriptional control to test the functional link between TET activity and memory (NIMH Strategy 1.1, Research Priority D; NIMH Strategy 1.2, Research Priority B). Aim 1 will identify the sex-specific gene targets of TET1 and TET2-mediated DNA 5-hmC in the prefrontal cortex following fear learning, using next generation whole genome chromatin immunoprecipitation (ChIP) and hydroxymethylated DNA immunoprecipitation (hmeDIP) sequencing methods. Aim 2 will use cutting-edge CRISPR-dCas9 technology to manipulate the expression of Tet1 and Tet2 in the prefrontal cortex of males and females during trace fear conditioning, which will determine the sex-dependent functional role of cortical TET1 and TET2 in fear memory formation. The proposed research is significant because it is expected to provide a (epi)genomic map of memory formation in a sexually dimorphic brain region, the medial prefrontal cortex, that is needed for understanding and even identifying new genetic biomarkers of sex-biased emotional and cognitive deficits in psychiatric illness.

项目概要/摘要创伤后应激障碍 (PTSD) 影响着近 8% 的人口，并且在女性中更为普遍比男人。造成这种性别偏见的神经生物学因素在很大程度上尚不清楚。这个项目根据 NIMH 战略目标 1，通过确定转录如何解决这一差距男性和女性对记忆相关基因的调节在支持恐惧记忆方面存在差异。最近我们的研究小组证明，雄性和雌性大鼠前额叶内的信号传导机制存在差异恐惧记忆形成过程中的皮层（PFC），我们的初步发现表明性别差异前额叶基因的表观遗传修饰。目前，情景记忆的转录调控人们对认知系统知之甚少，而性对这一动态过程的影响几乎是未知的。这对开发针对创伤后应激障碍（PTSD）等疾病的有效治疗方法提出了重大挑战。目标该提案的目的是确定 DNA 羟甲基化酶 TET 酶如何功能性调节恐惧记忆形成并识别厌恶经历的性别特异性甲基组学特征。 DNA 5- 羟甲基化 (5-hmC) 是细胞中活性（增加）转录的主要调节因子，最近被与大脑中恐惧记忆的形成有关。然而，在参与度方面是否存在性别差异？恐惧记忆形成过程中的 DNA 5-hmC 机制仍然模棱两可。在我们的初步研究中我们发现在大鼠前额皮质中，DNA 羟甲基化酶 Tet2 在雌性中增加，而 Tet1 在雌性中减少男性遵循微量恐惧调节范式学习。中心假设是 TET 介导的前额皮质中性别特异性基因靶标的 DNA 5-羟甲基化促进恐惧的形成记忆。该方法使用无偏见的全基因组分析（NIMH 策略 1.2，研究优先级 B）与病毒介导的转录控制相结合，测试 TET 活性和记忆（NIMH 策略 1.1，研究优先级 D；NIMH 策略 1.2，研究优先级 B）。目标 1 将确定恐惧后前额皮质中 TET1 和 TET2 介导的 DNA 5-hmC 的性别特异性基因靶标学习，使用下一代全基因组染色质免疫沉淀 (ChIP) 和羟甲基化 DNA 免疫沉淀 (hmeDIP) 测序方法。目标 2 将使用尖端的 CRISPR-dCas9 技术操纵男性和女性前额皮质中 Tet1 和 Tet2 的表达追踪恐惧调节，这将决定皮质 TET1 和 TET2 的性别依赖性功能作用恐惧记忆的形成。拟议的研究意义重大，因为它有望提供（表观）基因组学性别二态性大脑区域（内侧前额叶皮层）的记忆形成图，这是了解甚至识别性别偏见情绪和认知缺陷的新遗传生物标志物精神疾病。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Epigenetic Mechanisms in Memory and Cognitive Decline Associated with Aging and Alzheimer's Disease.

DOI：
10.3390/ijms222212280
发表时间：
2021-11-13
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Maity S;Farrell K;Navabpour S;Narayanan SN;Jarome TJ
通讯作者：
Jarome TJ

Females, but not males, require protein degradation in the hippocampus for contextual fear memory formation.

DOI：
10.1101/lm.053429.121
发表时间：
2021-08
期刊：
Learning & memory (Cold Spring Harbor, N.Y.)
影响因子：
0
作者：
Martin K;Musaus M;Navabpour S;Gustin A;Ray WK;Helm RF;Jarome TJ
通讯作者：
Jarome TJ

Sex-differences in proteasome-dependent K48-polyubiquitin signaling in the amygdala are developmentally regulated in rats.

DOI：
10.1186/s13293-023-00566-z
发表时间：
2023-11-10
期刊：
BIOLOGY OF SEX DIFFERENCES
影响因子：
7.9
作者：
Farrell, Kayla;Auerbach, Aubrey;Liu, Catherine;Martin, Kiley;Pareno, Myasia;Ray, W. Keith;Helm, Richard F.;Biase, Fernando;Jarome, Timothy J.
通讯作者：
Jarome, Timothy J.

Males and females differ in the regulation and engagement of, but not requirement for, protein degradation in the amygdala during fear memory formation.

DOI：
10.1016/j.nlm.2021.107404
发表时间：
2021-04
期刊：
Neurobiology of learning and memory
影响因子：
2.7
作者：
Devulapalli R;Jones N;Farrell K;Musaus M;Kugler H;McFadden T;Orsi SA;Martin K;Nelsen J;Navabpour S;O'Donnell M;McCoig E;Jarome TJ
通讯作者：
Jarome TJ

Protein SUMOylation is a sex-specific regulator of fear memory formation in the amygdala.

DOI：
10.1016/j.bbr.2022.113928
发表时间：
2022-07-26
期刊：
BEHAVIOURAL BRAIN RESEARCH
影响因子：
2.7
作者：
Gustin, Aspen;Navabpour, Shaghayegh;Farrell, Kayla;Martin, Kiley;DuVall, Jessica;Ray, W. Keith;Helm, Richard F.;Jarome, Timothy J.
通讯作者：
Jarome, Timothy J.