Social regulation of transcription and methylation networks in the brain

 描述（由申请人提供）：社会关系是人类福祉的重要组成部分，可以以积极和消极的方式影响健康，但其潜在的生物学机制尚不清楚。更好地了解社会行为背后的遗传和表观遗传系统将改善以社会认知和行为缺陷为特征的神经精神疾病的诊断和治疗。例如，自闭症谱系障碍、精神分裂症和抑郁症都存在社会交往问题。基因表达的表观遗传修饰与这些疾病有关，包括性类固醇作用，可能反映了其患病率的性别差异。脊椎动物的社会行为是由保守的神经回路网络，统称为“社会行为网络”，其中包括视前区，前，腹内侧亚区下丘脑内协调。Astatotilapia burtoni是一种非洲慈鲷鱼，它是一个很好的模型系统，可以用来理解社会行为如何改变大脑。男性存在的两个社会控制的，可逆的，具有丰富的，量化不同的行为剧目的表型之一：生殖能力占主导地位的（D）男性和生殖能力不占主导地位的（ND）男性。先前的研究已经确定了A. burtoni下丘脑作为社会地位的函数。这项研究将利用下一代测序技术，从A. burtoni雄性最近从ND上升到D状态，比较了有和没有类固醇阻滞剂的动物。这种药理学干预将通过基因转录阐明类固醇对行为的关键作用。一种生物学上的灵感， 基于约束网络的分析框架将以无偏见的方式将分子信息与来自同一鱼的行为和生理数据相结合。具体目标将是确定对改变社会行为重要的大规模基因表达和甲基化模式，并测试有关类固醇作用下游的转录效应如何驱动与社会地位相关的行为和生理变化的假设。基因本体分析将表征由社会背景共同调控的基因组的功能，并识别表明共同调控机制的序列特征（例如转录因子结合位点）。结果将用于设计机制随访研究。总的来说，这些结果将完善我们对基因表达，表观遗传调控和社会环境之间关系的一般理解，并确定分子系统和社会行为之间的特定联系。这项研究还将深入了解基因表达和甲基化之间的相互作用，因为它与疾病和社会行为的演变有关。

 DESCRIPTION (provided by applicant): Social relationships are an essential part of human well-being and can affect health in both positive and negative ways, but the underlying biological mechanisms are not well understood. A better understanding of the genetic and epigenetic systems that underlie social behavior would improve diagnosis and treatment of neuropsychiatric disorders that are characterized by deficits in social cognition and behavior. For example, autism spectrum disorders, schizophrenia, and depression share problems of social interactions. Epigenetic modifications of gene expression have been implicated in these disorders, including with respect to sex steroid action, likely reflecting the gender differences i their prevalence. Vertebrate social behavior is coordinated by conserved networks of neural circuits collectively known as the "social behavior network", which includes the preoptic, anterior, and ventromedial subregions within the hypothalamus. Astatotilapia burtoni, an African cichlid fish, is a well-established model system for understanding how social behavior changes the brain. Males exist as one of two socially controlled, reversible, phenotypes with rich, quantifiably distinct behavioral repertoires: reproductively competent dominant (D) males and reproductively incompetent non-dominant (ND) males. Previous studies have identified differences in gene expression and DNA methylation in A. burtoni hypothalamus as a function of social status. The proposed study will greatly extend prior efforts by taking advantage of next-generation sequencing technologies to generate gene expression data and genome-wide DNA methylation maps from the hypothalamus of A. burtoni males recently ascended from ND to D status, comparing animals with and without a steroid blocker. This pharmacological intervention will illuminate key steroid effects on behavior via gene transcription. A biologically inspired and constrained network-based analysis framework will integrate molecular information with behavioral and physiological data from the same fish in an unbiased manner. The specific goals will be to identify large-scale gene expression and methylation patterns that are important for altering social behavior, and to test hypotheses about how transcriptional effects downstream of steroid action drive behavioral and physiological changes related to social status. Gene ontology analysis will characterize functions of groups of genes co-regulated by social context, and identify sequence features (e.g. transcription factor binding sites) that suggest common regulatory mechanisms. Results will be used to design mechanistic follow-up studies. Overall, the results will refine our general understanding of the relationships between gene expression, epigenetic regulation, and the social environment, as well as identify specific connections between molecular systems and social behaviors. This research will also provide insight into the interplay between gene expression and methylation as it pertains to disease and the evolution of social behavior.