Defining the Molecular Origins of Developmental Brain Disorders

定义大脑发育障碍的分子起源

基本信息

  • 批准号:
    9767283
  • 负责人:
  • 金额:
    $ 3.31万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-01 至 2020-08-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY / ABSTRACT Only a small percentage of the autism spectrum disorders appear to have a clear genetic etiology (~25%), leaving a majority of cases with unclear origins. Alterations in environmentally sensitive epigenetic marks (e.g., DNA methylation) have been implicated in mental illness, including autism. A novel epigenetic mark, 5- hydroxymethylcytosine (5hmC), is enriched in neurons and is associated with active transcription of neuronal genes. While numerous studies have profiled 5hmC and found links to neurological disorders, less effort has been invested in determining the functional role of 5hmC, as it pertains to gene expression. As a result, the full functional potential of 5hmC modifications has yet to be realized in outcomes related to behavior. A recent genome-wide profile of striatal 5hmC in an autism mouse model (i.e., a Cntnap2-/- homozygote) that exhibits core autism features, including deficits in striatal GABAergic signaling, revealed a genome-wide disruption of 5hmC in the orthologs of a remarkable number of genes implicated in human autism (N=68/233). Thus, these data suggest a role for 5hmC-mediated epigenetic modulation in the pathogenesis of autism and represent a critical step toward understanding the genome-wide molecular consequences of a homozygous mutation that results in an autism-like phenotype. Notably, Cntnap2+/- heterozygous mutant mice lack autistic-like features. Since 5hmC levels are environmentally sensitive, these findings led to the hypothesis that Cntnap2+/- heterozygous mice subjected to an early environmental stress would have disruptions in 5hmC and may exhibit autistic-like behaviors similar to the Cntnap2-/- homozygous mutant. To test this hypothesis, beginning at embryonic day 12, Cntnap2+/- heterozygous mice were subjected to seven days of prenatal stress and subsequently examined for adult behaviors. Unlike wild-type littermates, prenatally stressed female Cntnap2+/- heterozygous mice exhibited social deficits. In addition, genomic profiling revealed disruptions in 5hmC throughout the striatal genome, which were similar to those seen in Cntnap2-/- homozygous mice. Finally, integration of the above data with striatal gene expression data revealed that differential hydroxymethylation correlated with altered transcript levels of genes shown to contribute to the deficits in GABAergic signaling and social behavior of the Cntnap2-/- homozygous mutant mouse (e.g., GABA receptors and Oxytocin). Thus, these data demonstrate that gene by environment interactions lead to deficits in social interactions and suggest that 5hmC levels likely contribute to this outcome. Here, the proposed studies will: 1) identify the functional role of 5hmC in social deficits resulting from prenatal stress; and 2) identify the contribution of oxytocin in social deficits exhibited following prenatal stress. These findings will identify stress-related molecular targets in the brain that are influenced by environmentally sensitive epigenetic mechanisms and may be involved in the etiology of developmental brain disorders. Importantly, the plan builds on the applicant's training in genomic studies, combining genomics will in-depth training in molecular and behavioral approaches.
项目摘要/摘要 只有一小部分自闭症谱系障碍似乎有明确的遗传病因(约25%), 留下了大部分来历不明的案例。环境敏感的表观遗传标记的改变(例如, DNA甲基化)与包括自闭症在内的精神疾病有关。一个新的表观遗传标记,5- 羟甲基胞嘧啶(5hmC)在神经元中含量丰富,并与神经元的活性转录有关 基因。虽然许多研究已经测定了5HmC并发现与神经疾病有关,但较少的努力 一直致力于确定5hmC的功能作用,因为它与基因表达有关。因此,完整的 5hmC修饰的功能潜力尚未在与行为相关的结果中实现。最近 自闭症小鼠模型(即cntnap2-/-纯合子)纹状体5hmC的全基因组图谱 自闭症的核心特征,包括纹状体GABA能信号的缺陷,揭示了全基因组范围的 在与人类自闭症有关的大量基因的直系物中存在5hmC(N=68/233)。因此,这些 数据表明,5hmC介导的表观遗传调节在自闭症的发病机制中发挥了作用,并代表了一种 了解纯合子突变的全基因组分子后果的关键一步 导致自闭症样表型。值得注意的是,cntnap2+/-杂合突变小鼠缺乏自闭症样特征。 由于5hmC水平对环境敏感,这些发现导致了cntnap2+/-的假设 受到早期环境应激的杂合子小鼠在5hmC会出现中断,并可能 表现出类似于cntnap2-/-纯合子突变体的自闭症样行为。为了检验这一假设,从 在胚胎第12天,cntnap2+/-杂合子小鼠受到7天的产前应激和 随后检查了成年人的行为。与野生型产仔不同,产前应激的雌性cntnap2+/- 杂合子小鼠表现出社交缺陷。此外,基因组图谱显示5hmC的中断 在整个纹状体基因组中,这与在cntnap2/-纯合子小鼠中看到的相似。最后, 将上述数据与纹状体基因表达数据相结合,表明差异羟甲基化 与基因转录水平的改变有关,这些基因被证明是导致GABA能信号和 Cntnap2-/-纯合突变小鼠的社会行为(例如,GABA受体和催产素)。因此,这些 数据表明,基因与环境的相互作用会导致社会互动的缺陷,并表明 5hmC水平可能是导致这一结果的原因。在这里,拟议的研究将:1)确定功能 5hmC在产前应激导致的社会缺陷中的作用;和2)确定 社会缺陷中的催产素在产前应激后表现出来。这些发现将确定与压力有关的 大脑中受环境敏感的表观遗传机制影响的分子靶点,可能 参与发育性大脑疾病的病因学研究。重要的是,该计划建立在申请人的 在基因组研究方面的培训,结合基因组学将在分子和行为方法方面进行深入的培训。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Species-Specific 5 mC and 5 hmC Genomic Landscapes Indicate Epigenetic Contribution to Human Brain Evolution.
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Andy Madrid其他文献

Andy Madrid的其他文献

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{{ truncateString('Andy Madrid', 18)}}的其他基金

Defining the Molecular Origins of Developmental Brain Disorders
定义大脑发育障碍的分子起源
  • 批准号:
    9332052
  • 财政年份:
    2017
  • 资助金额:
    $ 3.31万
  • 项目类别:

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