A human genome-wide screen for transgenerational epigenetic inheritance

跨代表观遗传的人类全基因组筛选

• 批准号: BB/H012494/1
• 负责人: Vardhman Rakyan
• 金额: $ 35.69万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH012494%2F1
• 关键词: human; genome; wide; screen; transgenerational

During the last 50 years, several studies have challenged the view that DNA is the sole biological unit of heredity in multi-cellular organisms such as mammals. In these studies, inter-individual phenotypic differences were observed that could not be explained by genetic or environmental heterogeneity and yet, surprisingly, were passed on to the offspring. We are now beginning to realize that the biological mechanisms at the heart of these phenomena are epigenetic. Epigenetic modifications, such as the addition of methyl groups to the DNA, occur naturally and stably influence genome function without changing the underlying DNA sequence. Specifically, epigenetic modifications play central roles in regulating gene expression, and therefore it is not surprising that the cell carefully controls when and where in the genome epigenetic modifications are established. However, recent evidence suggests that epigenetic modifications in mammals can be perturbed by environmental or stochastic factors, in some cases correlating with altered phenotypes in the individual. But could such epigenetic variants, be transmitted to the offspring? Theoretically, such epigenetic variants should not be passed on to the next generation as they might interfere with embryonic development of the offspring. Indeed, during normal mammalian development, epigenetic modifications are reprogrammed during early embryogenesis. However, studies in mouse models show that occasionally epigenetic variants escape this reprogramming event and persist in the cells of the offspring i.e. epigenetic inheritance - biological inheritance that is not encoded strictly in the DNA sequence. If common, epigenetic inheritance could have a significant impact on phenotypic outcomes in the context of both health and disease. However, conclusive evidence of this phenomenon in humans is still lacking. To date, only three single-gene studies have claimed transgenerational epigenetic inheritance-like effects in humans, and even these have been controversial. The main stumbling blocks have been access to: (i) suitable human cohorts in which epigenetic inheritance can be distinguished from the effects of genetics or environment; (ii) technologies for performing relatively unbiased experiments to search for these epigenetic variants. We intend to perform the first-ever systematic large-scale study of epigenetic inheritance in humans. The experimental design uses a powerful approach that integrates a cohort of identical twins and their offspring, cutting-edge genomics technologies, and custom computational biology methodologies. The results of our study will yield crucial insights into the phenomenon of epigenetic inheritance, thereby significantly impacting on our understanding of the biological basis of heritable phenotypic variation in humans.

在过去的50年中，几项研究挑战了DNA是多细胞生物（例如哺乳动物）中遗传的唯一生物学单位。在这些研究中，观察到了个体间表型差异，这些差异无法通过遗传或环境异质性来解释，但是令人惊讶的是，后代传给了后代。我们现在开始意识到，这些现象的核心是表观遗传学的。表观遗传修饰，例如向DNA中添加甲基，自然而稳定地影响基因组功能，而无需改变潜在的DNA序列。具体而言，表观遗传修饰在调节基因表达中起着核心作用，因此，仔细控制基因组表观遗传修饰中的何时何地，毫不奇怪。但是，最近的证据表明，哺乳动物的表观遗传修饰可能受到环境或随机因素的干扰，在某些情况下，与个人表型的改变相关。但是，这种表观遗传变体可以传播到后代吗？从理论上讲，这种表观遗传变体不应传递给下一代，因为它们可能会干扰后代的胚胎发育。实际上，在正常的哺乳动物发育期间，在早期胚胎发生过程中对表观遗传修饰进行了重编程。然而，在小鼠模型中的研究表明，偶尔表观遗传变体逃脱了重编程事件，并持续存在于后代的细胞中，即表观遗传遗传 - 生物遗传，这些遗传并未严格地在DNA序列中编码。如果常见，在健康和疾病的背景下，表观遗传可能会对表型结局产生重大影响。但是，仍然缺乏这种现象的确定证据。迄今为止，只有三项单基因研究声称在人类中具有跨代表观遗传的遗传效应，甚至这些遗传效应也是有争议的。主要的绊脚石已进入：（i）可以将表观遗传遗传与遗传学或环境的影响区分开的合适人类同类群体； （ii）进行相对无偏见的实验以搜索这些表观遗传变体的技术。我们打算对人类的表观遗传遗传进行第一个系统的大规模研究。实验设计采用了一种强大的方法，该方法整合了一系列相同的双胞胎及其后代，尖端的基因组学技术和定制的计算生物学方法论。我们的研究结果将产生对表观遗传遗传现象的关键见解，从而显着影响我们对人类遗传表型变异的生物学基础的理解。

项目成果

Novel DNA methylation profiles associated with key gene regulation and transcription pathways in blood and placenta of growth-restricted neonates.

• DOI: 10.4161/15592294.2014.989741
• 发表时间: 2015
• 期刊: Epigenetics
• 影响因子: 3.7
• 作者: Hillman SL;Finer S;Smart MC;Mathews C;Lowe R;Rakyan VK;Hitman GA;Williams DJ
• 通讯作者: Williams DJ

Marmal-aid--a database for Infinium HumanMethylation450.

• DOI: 10.1186/1471-2105-14-359
• 发表时间: 2013-12-12
• 期刊: BMC bioinformatics
• 影响因子: 3
• 作者: Lowe R;Rakyan VK
• 通讯作者: Rakyan VK

Inactive or moderately active human promoters are enriched for inter-individual epialleles.

• DOI: 10.1186/gb-2013-14-5-r43
• 发表时间: 2013-05-25
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Gemma C;Ramagopalan SV;Down TA;Beyan H;Hawa MI;Holland ML;Hurd PJ;Giovannoni G;Leslie RD;Ebers GC;Rakyan VK
• 通讯作者: Rakyan VK

The human blood DNA methylome displays a highly distinctive profile compared with other somatic tissues.

• DOI: 10.1080/15592294.2014.1003744
• 发表时间: 2015
• 期刊: Epigenetics
• 影响因子: 3.7
• 作者: Lowe R;Slodkowicz G;Goldman N;Rakyan VK
• 通讯作者: Rakyan VK