Iterative somatic epigenetic programming of behavior across multiple generations

多代行为的迭代体细胞表观遗传编程

• 批准号: 9299333
• 负责人: Miklos Toth
• 金额: $ 24.99万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-06 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9299333
• 关键词: Adult; Alleles; Animals; Antibodies; Anxiety; Autistic Disorder; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Behavior; Behavioral; Biological; Bone Marrow; Brain; Child; Chromatin; DNA Methylation; DNA Sequence; Data; Development; Disease; Environment; Epigenetic Process; Exposure to; Female; Fetus; Generations; Genetic; Genetic Polymorphism; Germ Cells; Goals; Immune; Immune system; Immunologics; Incidence; Inflammation; Interruption; Left; Mammals; Mental disorders; Metabolic; Modeling; Mothers; Mutation; Neonatal; Parents; Pathologic; Phenotype; Placenta; Pregnancy; Process; Production; Reporting; Small RNA; Stress; Symptoms; Testing; Work; anxiety-like behavior; autoreactivity; base; brain parenchyma; cardiovascular risk factor; drug of abuse; environmental chemical; epidemiology study; exosome; experience; experimental study; fetal; immune activation; intergenerational; monocyte; neonatal Fc receptor; neuropsychiatry; neutrophil; non-genetic; novel; offspring; prevent; receptor; reconstitution; trait; transmission process

Abstract Inheritance is typically associated with the Mendelian transmission of information from parents to offspring by alleles, but empirical data clearly suggest that traits can be acquired from ancestors by mechanisms that do not involve DNA sequence. Information that is non-genetically transmitted includes parental experience, exposure to environmental chemicals, drugs of abuse, and parental mutations and polymorphisms that change the parental environment. Non-genetic inheritance has been observed for a wide range of diseases, including psychiatric disorders. Non-genetic inheritance is not limited to the first generation of the progeny, but can involve the grandchildren and even further generations. While multigenerational transmission of traits is typically believed to be gametic, we previously showed that it can occur iteratively through a somatic mechanism during gestation. We refer to this mode of transmission of behavioral traits as iterative somatic programming. We recently found that multigenerational non-genetic transmission of anxiety and stress traits is associated and perhaps caused by maternal autoimmunity perpetuating from one generation to the next. We hypothesize that maternal autoreactive antibodies cross the placenta and cause inflammation in the offspring, manifesting as anxiety in adulthood. This hypothesis will be tested by interrupting the cycle of iterative programming of offspring anxiety, by mitigating the maternal autoimmunity and/or interfering with the transfer of the maternal autoantibodies to the fetus by various immunological approaches. This mechanistic work may help explain the increased incidence of autism and neuropsychiatric conditions in children of mothers with autoimmune diseases. Taken together, our experiments test a novel mechanism that may contribute to the iterative somatic transmission of pathological behavioral traits, particularly those associated with maternal autoimmunity. In contrast to genetic, somatic inheritance of traits is not inevitable, and therefore could be prevented, once the underlying mechanism is better understood.

摘要 遗传通常与孟德尔式的信息传递有关， 后代的等位基因，但经验数据清楚地表明，性状可以从祖先获得， 不涉及DNA序列的机制。非基因传播的信息包括 父母的经验，暴露于环境化学品，滥用药物，和父母的突变， 改变父母环境的多态性。非遗传性遗传已经被观察到， 广泛的疾病，包括精神疾病。非基因遗传不限于第一种 后代的后代，但可以涉及孙子，甚至更远的几代。而 性状的多代传递通常被认为是配子传递，我们之前已经证明了这一点 在妊娠期间通过躯体机制反复发生。我们把这种模式称为 行为特征的传递就像迭代的体细胞编程。我们最近发现， 焦虑和压力特征的多代非遗传传递是相关的，可能是由 母亲的自身免疫力会代代相传我们假设母亲 自身反应性抗体穿过胎盘并引起后代炎症，表现为 成年期的焦虑这一假设将通过中断迭代编程的循环来测试， 后代的焦虑，通过减轻母体自身免疫和/或干扰转移的 母体自身抗体对胎儿的各种免疫学方法。这种机械工作可以 有助于解释母亲的孩子自闭症和神经精神疾病的发病率增加 自身免疫性疾病总之，我们的实验测试了一种新的机制， 病理行为特征的反复体细胞传播，特别是那些与 母体自身免疫与遗传相反，性状的体细胞遗传不是不可避免的， 因此，一旦更好地了解了潜在的机制，就可以预防。