Genomic imprinting in circuits for social behavior

修改后的项目摘要/摘要部分 该项目的R00阶段将在伊利诺伊大学厄巴纳-香槟分校兽医学院比较生物科学系进行。严重的精神障碍，如精神分裂症(SZ)和严重抑郁症，涉及异常的社会行为，通常发生在青春期之后。SZ的遗传危险因素在受影响的个体中经常是杂合子的，临床表型可能是高度可变的。然而，导致表型差异的因素和这些疾病的发病时间却知之甚少。基因组印记是一种表观遗传机制，导致某些基因的母系或父系等位基因优先表达。印记会引起亲本效应，从而影响遗传突变的表型。规范的印记涉及完全沉默一个父母的等位基因，并影响少数基因。然而，作者的实验室发现，在小鼠中，数百个表现出母系或父系等位基因表达偏差的基因。这种现象被称为非正则印迹。与肝脏或肌肉相比，非规范印迹在大脑中高度丰富。利用一种新的等位基因特异性原位杂交方法，作者发现非规范印记基因在大脑中的细胞亚群中表现出单等位基因的表达，这表明印记是一种高度细胞类型特异性的印记形式。目前，尚不清楚非规范印记是否是大脑中一种细胞类型的特定形式的印记。此外，该领域不知道非规范的印记是否会在青春期改变，或者社会行为是否会受到影响。作者发现酪氨酸羟基酶(Th)和多巴脱羧酶(DDC)是非规范的印迹基因，在大脑的特定区域具有母体等位基因偏向。TH和DDC合成单胺类神经递质，在社会行为和精神疾病中发挥重要作用。在这里，作者将检验一种假设，即单胺能回路中的非规范印记效应是一种高度细胞类型的特定印记形式，可以随着青春期发育的变化而改变，并通过在精神疾病中的作用来影响社会行为。目标1将确定非规范印记是否是下丘脑单胺系统中的一种细胞类型特定形式的印记，并使用单细胞RNAseq揭示每种单胺细胞类型中起作用的激素信号机制。目的2用RNAseq方法研究青春期前后视前区(POA)和弓状核(ARN)的非典型印迹是否发生改变。POA和ARN在青春期和社会行为中发挥着重要作用，初步数据表明，这些区域的非规范印记可以响应激素信号的变化。在目标3中，将使用DDC杂合突变小鼠来确定单胺回路中的非规范印记是否会影响后代的社会行为。将测试受精神疾病影响的社会行为，包括攻击性、社会认可度、社会奖励和生殖行为。

Modified Project Summary/Abstract Section The R00 phase of this project will be conducted at the University of Illinois, Urbana-Champaign in the Department of Comparative Biosciences, College of Veterinary Medicine. Major psychiatric disorders, such as schizophrenia (SZ) and major depression, involve abnormal social behaviors and onset typically occurs after puberty. The genetic risk factors for SZ are frequently heterozygous in affected individuals and the clinical phenotypes can be highly variable. However, the factors that contribute to phenotypic variance and the timing of the onset of these disorders are poorly understood. Genomic imprinting is an epigenetic mechanism that causes preferential expression of the maternal or paternal allele for some genes. Imprinting causes parent-of-origin effects that influence the phenotype of inherited mutations. Canonical imprinting involves complete silencing of one parent’s allele and impacts a small number of genes. However, the author’s lab discovered that hundreds of genes in the mouse that exhibit a maternal or paternal allele expression bias. This phenomenon is called noncanonical imprinting. Noncanonical imprinting is highly enriched in the brain compared to the liver or muscle. Using a novel allele-specific in situ hybridization approach, the author found that noncanonical imprinted genes exhibit monoallelic expression in subpopulations of cells in the brain, suggesting a highly cell-type specific form of imprinting. Currently, it is not known whether noncanonical imprinting is a cell-type specific form of imprinting in the brain. Further, the field does not know whether noncanonical imprinting can change at puberty or whether social behaviors are impacted. The author found that tyrosine hydroxylase (Th) and dopa decarboxylase (Ddc) are noncanonical imprinted genes with a maternal allele bias in specific regions of the brain. TH and DDC synthesize monoamine neurotransmitters, which have important roles in social behavior and mental illness. Here, the author will test the hypothesis that noncanonical imprinting effects in monoaminergic circuits are a highly cell-type specific form of imprinting that can change in response to pubertal development and impact social behaviors with roles in mental illness. Aim 1 will determine whether noncanonical imprinting is a cell-type specific form of imprinting in the monoamine system of the hypothalamus and uncover the hormone signaling mechanisms operational within each monoamine cell type using single-cell RNASeq. Aim 2 will determine whether noncanonical imprinting in the preoptic area (POA) and arcuate nucleus (ARN) changes at puberty by profiling imprinting before and after puberty using RNASeq methods. The POA and ARN play important roles in puberty and social behaviors and preliminary data shows that noncanonical imprinting can change in these regions in response to hormonal signaling. In Aim 3, Ddc heterozygous mutant mice will be used to determine whether noncanonical imprinting in monoamine circuits impacts offspring social behaviors. Social behaviors that are impacted in mental illness will be tested, including aggression, social recognition, social reward and reproductive behaviors.