Papale Ligia A, Madrid Andy, Li Sisi, Alisch Reid S
a Department of Psychiatry , University of Wisconsin , Madison , WI , USA.
b Neuroscience Training Program , University of Wisconsin , Madison , WI , USA.
Epigenetics. 2017 Apr 3;12(4):264-276. doi: 10.1080/15592294.2017.1285986. Epub 2017 Jan 27.
Environmental stress contributes to the development of psychiatric disorders, including posttraumatic stress disorder and anxiety. While even acute stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive DNA modification that is highly enriched in the brain and is associated with active transcription of neuronal genes. Here we examined behavioral and molecular alterations in adult mice that experienced an early-life stress before weaning (postnatal day 12 to 18) and found anxiety-like behaviors in adult female mice that were accompanied by correlated disruptions of hypothalamic 5hmC and gene expression in 118 genes, revealing potentially functional 5hmC (i.e., gene regulation). These genes are known and potentially novel stress-related targets, including Nr3c2, Nrxn1, Nfia, and Clip1, that have a significant enrichment for neuronal ontological functions, such as neuronal development and differentiation. Sequence motif predictions indicated that 5hmC may regulate gene expression by mediating transcription factor binding and alternative splicing of many of these transcripts. Together, these findings represent a critical step toward understanding the effects of early environment on the neuromolecular mechanisms that underlie the risk to develop anxiety disorders.
环境应激会促使包括创伤后应激障碍和焦虑症在内的精神疾病的发展。即使是急性应激也会改变基因表达，然而这些变化背后的分子机制在很大程度上仍不为人知。5-羟甲基胞嘧啶（5hmC）是一种新型的对环境敏感的DNA修饰，在大脑中高度富集，并且与神经元基因的活跃转录相关。在此，我们研究了在断奶前（出生后第12至18天）经历过早期生活应激的成年小鼠的行为和分子变化，发现在成年雌性小鼠中存在类似焦虑的行为，同时伴有下丘脑5hmC的相关破坏以及118个基因的基因表达变化，揭示了潜在的功能性5hmC（即基因调控）。这些基因是已知的以及潜在的与应激相关的新靶点，包括Nr3c2、Nrxn1、Nfia和Clip1，它们在神经元本体功能（如神经元发育和分化）方面有显著富集。序列基序预测表明，5hmC可能通过介导转录因子结合以及许多这些转录本的可变剪接来调节基因表达。总之，这些发现代表了在理解早期环境对构成焦虑症发病风险基础的神经分子机制的影响方面迈出的关键一步。
