Mustafin R N, Kazantseva A V, Enikeeva R F, Malykh S B, Khusnutdinova E K
Bashkir State Medical University, Ufa, Russia.
Institute of Biochemistry and Genetics - Subdivision of the Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
Vavilovskii Zhurnal Genet Selektsii. 2020 Feb;24(1):87-95. doi: 10.18699/VJ20.599.
The present review describes longitudinal studies of cognitive traits and functions determining the causes of their variations and their possible correction to prevent cognitive impairment. The present study reviews the involvement of such environmental factors as nutrition, prenatal maternal stress, social isolation and others in cognitive functioning. The role of epigenetic factors in the implementation of environmental effects in cognitive characteristics is revealed. Considering the epigenome significance, several studies were focused on the design of substances affecting methylation and histone modification, which can be used for the treatment of cognitive disorders. The appropriate correction of epigenetic factors related to environmental differences in cognitive abilities requires to determine the mechanisms of chromatin modifications and variations in DNA methylation. Transposons representing stress-sensitive DNA elements appeared to mediate the environmental influence on epigenetic modifications. They can explain the mechanism of transgenerational transfer of information on cognitive abilities. Recently, large-scale meta-analyses based on the results of studies, which identified genetic associations with various cognitive traits, were carried out. As a result, the role of genes actively expressed in the brain, such as BDNF, COMT, CADM2, CYP2D6, APBA1, CHRNA7, PDE1C, PDE4B, and PDE4D in cognitive abilities was revealed. The association between cognitive functioning and genes, which have been previously involved in developing psychiatric disorders (MEF2C, CYP2D6, FAM109B, SEPT3, NAGA, TCF20, NDUFA6 genes), was revealed, thus indicating the role of the similar mechanisms of genetic and neural networks in both normal cognition and cognitive impairment. An important role in both processes belongs to common epigenetic factors. The genes involved in DNA methylation (DNMT1, DNMT3B, and FTO), histone modifications (CREBBP, CUL4B, EHMT1, EP300, EZH2, HLCS, HUWE1, KAT6B, KMT2A, KMT2D, KMT2C, NSD1, WHSC1, and UBE2A) and chromatin remodeling (ACTB, ARID1A, ARID1B, ATRX, CHD2, CHD7, CHD8, SMARCA2, SMARCA4, SMARCB1, SMARCE1, SRCAP, and SS18L1) are associated with increased risk of psychiatric diseases with cognitive deficiency together with normal cognitive functioning. The data on the correlation between transgenerational epigenetic inheritance of cognitive abilities and the insert of transposable elements in intergenic regions is discussed. Transposons regulate genes functioning in the brain due to the processing of their transcripts into non-coding RNAs. The content, quantity and arrangement of transposable elements in human genome, which do not affect changes in nucleotide sequences of protein encoding genes, but affect their expression, can be transmitted to the next generation.
本综述描述了认知特征和功能的纵向研究，确定了其变异的原因以及为预防认知障碍而进行可能矫正的方法。本研究回顾了营养、产前母亲压力、社会隔离等环境因素在认知功能中的作用。揭示了表观遗传因素在认知特征中环境效应的实现过程中的作用。考虑到表观基因组的重要性，多项研究聚焦于设计影响甲基化和组蛋白修饰的物质，这些物质可用于治疗认知障碍。与认知能力环境差异相关的表观遗传因素的适当矫正需要确定染色质修饰和DNA甲基化变异的机制。转座子作为应激敏感的DNA元件似乎介导了环境对表观遗传修饰的影响。它们可以解释认知能力信息的代际传递机制。最近，基于确定了与各种认知特征的遗传关联的研究结果进行了大规模的荟萃分析。结果揭示了在大脑中活跃表达的基因，如脑源性神经营养因子（BDNF）、儿茶酚-O-甲基转移酶（COMT）、细胞粘附分子2（CADM2）、细胞色素P450 2D6（CYP2D6）、衔接蛋白相关蛋白1（APBA1）、α7烟碱型乙酰胆碱受体（CHRNA7）、磷酸二酯酶1C（PDE1C）、磷酸二酯酶4B（PDE4B）和磷酸二酯酶4D（PDE4D）在认知能力中的作用。揭示了认知功能与先前参与精神疾病发生的基因（MEF2C基因（肌细胞增强因子2C）、CYP2D6基因、FAM109B基因（家族性血小板减少伴精神发育迟滞1基因）、SEPT3基因（septin 3）、NAGA基因（N-乙酰神经氨酸α-2,8-唾液酸转移酶6）、TCF20基因（转录因子20）、NDUFA6基因（NADH脱氢酶[泛醌]1α亚基6））之间的关联，从而表明遗传和神经网络的相似机制在正常认知和认知障碍中的作用。共同的表观遗传因素在这两个过程中都起着重要作用。参与DNA甲基化的基因（DNA甲基转移酶1（DNMT1）、DNA甲基转移酶3B（DNMT3B）和肥胖相关基因（FTO））、组蛋白修饰的基因（CREB结合蛋白（CREBBP）、CUL4B泛素连接酶复合物亚基B（CUL4B）、组蛋白赖氨酸N-甲基转移酶1（EHMT1）、E1A结合蛋白P300（EP300）、zeste基因增强子同源物2（EZH2）、生物素合成酶（HLCS）、含WW和HECT结构域的泛素连接酶1（HUWE1）、赖氨酸乙酰转移酶6B（KAT6B）、赖氨酸甲基转移酶2A（KMT2A）、赖氨酸甲基转移酶2D（KMT2D）、赖氨酸甲基转移酶2C（KMT2C）、核受体结合SET结构域蛋白1（NSD1）、含锌指结构域的组蛋白赖氨酸N-甲基转移酶1（WHSC1）和泛素结合酶E2A（UBE2A））以及染色质重塑的基因（肌动蛋白β（ACTB）、AT丰富相互作用域1A（ARID1A）、AT丰富相互作用域1B（ARID1B）、α-地中海贫血/智力发育迟缓综合征X连锁蛋白（ATRX）、染色质解旋酶DNA结合蛋白2（CHD2）、染色质解旋酶DNA结合蛋白7（CHD7）、染色质解旋酶DNA结合蛋白8（CHD8）、SWI/SNF相关、基质相关、肌动蛋白依赖的染色质调节因子亚家族A成员2（SMARCA2）、SWI/SNF相关、基质相关、肌动蛋白依赖的染色质调节因子亚家族A成员4（SMARCA4）、SWI/SNF相关、基质相关、肌动蛋白依赖的染色质调节因子亚家族B成员1（SMARCB1）、SWI/SNF相关、基质相关、肌动蛋白依赖的染色质调节因子亚家族E成员1（SMARCE1）、SNF2相关CBP激活蛋白（SRCAP）和SS18样蛋白1（SS18L1））与伴有认知缺陷的精神疾病风险增加以及正常认知功能相关。讨论了认知能力的代际表观遗传遗传与基因间区域转座元件插入之间的相关性数据。转座子通过将其转录本加工成非编码RNA来调节大脑中的基因功能。人类基因组中转座元件的含量、数量和排列不影响蛋白质编码基因的核苷酸序列变化，但会影响其表达，这些转座元件可以传递给下一代。
