Novel epigenetic mechanisms in neuronal development and cognitive function

描述(申请人提供)：智力低下(MR)是一种由低智商(IQ&lt；70)诊断的病理性疾病。MR影响总人口的2%-3%，被认为是西方国家代价最高的疾病之一。尽管人类遗传学研究已经发现了过多的MR候选基因，其蛋白产物与不同的神经元过程有关，但这些MR候选基因中的许多调控认知功能的机制在很大程度上仍不清楚。表观遗传调控是最近出现的一种潜在的关键机制，表观遗传调控利用染色质修饰(DNA甲基化和组蛋白共价修饰)来产生基因转录活性的稳定变化，从而影响生物体的发育和生理。我们最近发现并鉴定了两种组蛋白去甲基酶，SMCX和PHF8，这两种酶在人类突变时都会导致智力低下，这表明组蛋白甲基化动力学在人类认知功能中起着重要作用。重要的是，我们最近产生了携带Smcx条件等位基因的小鼠。大脑中Smcx的消融会导致联想记忆的认知缺陷，并导致杏仁核神经元活动调节的基因表达减少。这项应用的主要目标之一是了解Smcx在学习和记忆中的细胞和分子作用机制。具体地说，我们将调查Smcx是否在各种记忆的形成中发挥普遍作用，包括短期记忆和长期记忆。我们将研究与Smcx丢失相关的记忆缺陷的细胞学基础。具体地说，我们将确定Smcx的缺失是否会影响神经发育以及突触/树突的结构和功能。我们还将进行电生理研究，以确定Smcx丢失对长时程增强和抑制的影响。这些实验将为Smcx调节记忆形成的细胞机制提供新的见解。我们还将研究Smcx调节学习和记忆的分子机制。我们将通过在全基因组水平上鉴定Smcx结合位点和受Smcx调控的基因表达网络来解决这个问题。根据我们的初步数据，将特别关注增强剂，其中Smcx可能通过其去甲基酶活性促进H3K4me1(一种功能作用不明确的组蛋白修饰)的产生，从而促进H3K4me1的产生 记忆形成过程中依赖活动的神经元基因转录。这些发现不仅将为SMCX如何调控认知提供重要的分子见解，还将阐明H3K4me1在增强子中的功能作用，这仍然是表观遗传学领域的一个突出问题。综上所述，拟议的研究将提供重要的新见解 转化为控制认知功能和行为的表观遗传机制，当出错时，会导致像MR这样的衰弱的人类疾病。

DESCRIPTION (provided by applicant): Mental retardation (MR) is a pathological condition diagnosed by a low intelligence quotient (IQ<70). MR affects 2-3% of the total population and is considered one of the most costly diseases in Western countries. Although human genetic studies have identified a plethora of MR candidate genes whose protein products are implicated in diverse neuronal processes, mechanisms by which many of these MR candidate genes regulate cognitive functions remain largely unclear. Epigenetic regulation has recently emerged as a potentially crucial mechanism in MR. Epigenetic regulation utilizes chromatin modifications (DNA methylation and histone covalent modifications) to produce stable changes in gene transcriptional activity, which impact development and physiology of the organism. We recently identified and characterized two histone demethylases, SMCX and PHF8, both causing mental retardation when mutated in humans, suggesting an important role for histone methylation dynamics in human cognitive function. Importantly, we have recently generated mice carrying a conditional allele of Smcx. Ablation of Smcx in the brain causes cognitive defects in associative memory and reduced expression of genes regulated by neuronal activity in amygdala. One of the main goals of this application is to understand the cellular and molecular mechanism of action of Smcx in learning and memory. Specifically, we will investigate if Smcx plays a general role in the formation of various memories, including short versus long term memory. We will investigate the cellular basis for the memory deficits associated with Smcx loss. Specifically, we will determine whether loss of Smcx impacts neural development as well as synaptic/dendritic structure and function. We will also carry out electrophysiological studies to determine the impact of Smcx loss on long-term potentiation and depression. These experiments will provide novel insights into the cellular mechanism by which Smcx regulates memory formation. We will also investigate the molecular mechanism by which Smcx regulates learning and memory. We will address this question by identifying, at genome-wide level, Smcx binding sites and gene expression networks regulated by Smcx. Based on our preliminary data, special attentions will be given to enhancers where Smcx may contribute to the generation of H3K4me1 (a defining histone modification with unclear functional role) via its demethylase activity and thus contribute to activity-dependent neuronal gene transcription during memory formation. Findings will not only provide significant molecular insights into how SMCX regulates cognition but also shed light on the functional role of H3K4me1 at enhancers, which remained an outstanding question in the epigenetic field. Taken together, the proposed studies will provide significant new insights into epigenetic mechanisms that control cognitive function and behavior, and, when go awry, cause debilitating human diseases such as MR.