精子miRNA介导抑郁症代际遗传的分子机制研究

Intergenerational epigenetic inheritance is the transmittance of information from one generation of an organism to the next (e.g., parent–child transmittance) that affects the traits of offspring without alteration of the primary structure of DNA (i.e., the sequence of nucleotides). Such transmission is proposed to occur mostly through alterations in the epigenomes of germ cells and is dependent on parental environment exposure or maternal in utero environment. However, the fundamental questions regarding the potential mechanisms responsible for the described phenomena remain to be elucidated. Depression, as a classic psychiatric disorder induced by both genetic and environmental effects, meets the basic characteristics of intergenerational inheritance. However, little is known about if depression in offspring can result from the father through a mechanism of intergenerational inheritance. Recent studies have shown that sperm miRNAs contribute to intergenerational inheritance of an acquired disorder, but the mechanism remains to be fully understood. In this project, we will investigate whether and how depression in father affects the psychic state and neurobehavioral function of their offspring. We will also investigate whether and how sperm miRNAs in father contribute to intergenerational inheritance of depression in offspring. Overall, our project may provide important information for understanding the influence of parental environment on human health. A better understanding of intergenerational epigenetic inheritance and the consequences of such acquired changes on individuals will likely provide insight into how gene–environment interactions shape development and physiological functions.

代际遗传是一种特殊的遗传性状和基因信息的传递方式，外界环境对亲本的刺激是主要诱因。抑郁症作为一种典型的遗传和环境因素共同诱发的精神类疾病，符合代际遗传的基本特征，由于抑郁症的经典遗传学规律长期未能阐释清晰，提示代际遗传可能是适合的新研究切入点。最新的科学发现显示了miRNA作为代际遗传介质的能力，但其作用机理并不清楚。基于此，本项目着眼于抑郁症的代际遗传现象，以精子miRNA的作用为主线，系统性研究精子内miRNA介导抑郁症代际遗传的分子机制和作用机理。前期结果显示压力诱导的雄性抑郁小鼠产生的子代具有抑郁易感现象；RNA测序显示抑郁小鼠精子的miRNA谱发生显著变化；分离抑郁小鼠精子小RNA，利用显微技术注射到正常受精卵并进行胚胎移植，其子代小鼠发生抑郁倾向；这些数据初步表明精子miRNA参与调控抑郁症代际遗传。本项目对阐释抑郁症的发病机理和研制靶向药物具有重要意义。

代际遗传是一种特殊的遗传性状和基因信息的传递方式，外界环境对亲本的刺激是主要诱因。抑郁症作为一种典型的遗传和环境因素共同诱发的精神类疾病，符合代际遗传的基本特征，由于抑郁症的经典遗传学规律长期未能阐释清晰，提示代际遗传可能是适合的新研究切入点。最新的科学发现显示了miRNA作为代际遗传介质的能力，但其作用机理并不清楚。基于此，本项目着眼于抑郁症的代际遗传现象，以精子miRNA的作用为主线，系统性研究精子内miRNA介导抑郁症代际遗传的分子机制和作用机理。研究结果显示压力诱导的雄性抑郁小鼠产生的子代具有抑郁易感现象；RNA测序显示抑郁小鼠精子的miRNA谱发生显著变化；分离抑郁小鼠精子小RNA，利用显微技术注射到正常受精卵并进行胚胎移植，其子代小鼠发生抑郁倾向；这些数据初步表明精子miRNA参与调控抑郁症代际遗传。本项目对阐释抑郁症的发病机理和研制靶向药物具有重要意义。