The DNA methylome of human sperm is distinct from blood with little evidence for tissue-consistent obesity associations.
The DNA methylome of human sperm is distinct from blood with little evidence for tissue-consistent obesity associations.
复制标题
DOI：
10.1371/journal.pgen.1009035
复制
发表时间：
2020-10
期刊：
影响因子：
4.5
通讯作者：
Williams DJ
中科院分区：
文献类型：
--
作者：
Åsenius F;Gorrie-Stone TJ;Brew A;Panchbhaya Y;Williamson E;Schalkwyk LC;Rakyan VK;Holland ML;Marzi SJ;Williams DJ
流行病学研究表明，父亲肥胖可能会增加生育小于胎龄儿的风险。在非人类哺乳动物中的研究表明，这种关联可能是由精子中影响后代在子宫内发育的DNA甲基化变化介导的。人类肥胖与外周血DNA甲基化差异相关然而，目前还不清楚这种差异DNA甲基化是否反映在精子中。我们使用Illumina MethylationEPIC阵列对来自瘦男性（发现n = 47;复制n = 21）和肥胖男性（n = 22）的匹配人类血液和精子进行横断面研究，以分析DNA甲基化的组织共变异，并识别肥胖相关的甲基化特征。我们发现人类血液和精子的DNA甲基化特征高度不一致，甲基化水平仅在少数CpG位点（~1%）相关。在大多数这些位点，DNA甲基化似乎受到遗传变异的影响。血液中与肥胖相关的DNA甲基化通常不会反映在精子中，肥胖与这两种组织的共变异模式改变或表观遗传老化加速无关。然而，发现了一个跨组织肥胖特异性高甲基化位点（cg 19357369; chr 4：2429884; P = 8.95 × 10−8; 2% DNA甲基化差异），阻止了复制和进一步研究。当与广泛的人类体细胞组织样本（n = 5，917）相比时，精子在转录调控富集的途径中显示出差异DNA甲基化。总的来说，人类精子显示出独特的DNA甲基化谱，这与匹配的外周血的DNA甲基化谱高度不一致，并且几乎不相关。我们观察到，肥胖只是名义上与精子中的差异DNA甲基化相关，因此表明精子DNA甲基化不太可能是代谢性状代际效应的介导者。主要在老鼠身上进行的研究表明，父亲的肥胖会通过父亲精子的变化影响后代的健康。目前尚不清楚这是否适用于人类。在这项研究中，我们检查了精瘦和肥胖男性的精子和血液，以了解肥胖是否会影响这两种组织中的DNA甲基化。DNA甲基化会影响基因功能，因此可能会影响后代的健康。我们发现，肥胖和精子中的DNA甲基化之间几乎没有联系。我们还发现，在肥胖个体血液中发现的DNA甲基化模式并不存在于肥胖男性的精子中。一般来说，整个基因组的DNA甲基化模式是完全不同的，两种组织之间不相关。最后，我们将精子中的DNA甲基化模式与许多其他组织中的DNA甲基化模式进行了比较，包括例如血液和大脑样本，并发现精子具有独特的DNA甲基化特征，该特征指向参与调节整体转录水平的基因。我们的结论是，肥胖可能不会影响精子中的DNA甲基化，虽然还需要更多的研究，如果父亲肥胖确实会影响孩子的健康，这个过程不太可能是由精子DNA甲基化介导的。
Epidemiological research suggests that paternal obesity may increase the risk of fathering small for gestational age offspring. Studies in non-human mammals indicate that such associations could be mediated by DNA methylation changes in spermatozoa that influence offspring development in utero. Human obesity is associated with differential DNA methylation in peripheral blood. It is unclear, however, whether this differential DNA methylation is reflected in spermatozoa. We profiled genome-wide DNA methylation using the Illumina MethylationEPIC array in a cross-sectional study of matched human blood and sperm from lean (discovery n = 47; replication n = 21) and obese (n = 22) males to analyse tissue covariation of DNA methylation, and identify obesity-associated methylomic signatures. We found that DNA methylation signatures of human blood and spermatozoa are highly discordant, and methylation levels are correlated at only a minority of CpG sites (~1%). At the majority of these sites, DNA methylation appears to be influenced by genetic variation. Obesity-associated DNA methylation in blood was not generally reflected in spermatozoa, and obesity was not associated with altered covariation patterns or accelerated epigenetic ageing in the two tissues. However, one cross-tissue obesity-specific hypermethylated site (cg19357369; chr4:2429884; P = 8.95 × 10−8; 2% DNA methylation difference) was identified, warranting replication and further investigation. When compared to a wide range of human somatic tissue samples (n = 5,917), spermatozoa displayed differential DNA methylation across pathways enriched in transcriptional regulation. Overall, human sperm displays a unique DNA methylation profile that is highly discordant to, and practically uncorrelated with, that of matched peripheral blood. We observed that obesity was only nominally associated with differential DNA methylation in sperm, and therefore suggest that spermatozoal DNA methylation is an unlikely mediator of intergenerational effects of metabolic traits. Research primarily conducted in mice suggests that obesity in fathers can have effects on the health of their offspring via changes in the fathers’ sperm. It is not confirmed whether this is true for humans. In this study, we examined sperm and blood from lean and obese men to understand whether obesity affects DNA methylation in both tissues. DNA methylation can impact on gene function and therefore may affect offspring health. We found that there was almost no association between obesity and DNA methylation in sperm. We also showed that DNA methylation patterns found in the blood of obese individuals are not present in sperm from obese men. Generally, DNA methylation patterns across the whole genome were completely different and uncorrelated between the two tissues. Lastly, we compared DNA methylation patterns in sperm to those in many other tissues, including for example blood and brain samples, and found that sperm has a unique signature of DNA methylation—one that points to genes involved in regulating overall levels of transcription. We conclude that obesity probably does not affect DNA methylation in sperm and that, although more research is needed, if obesity in fathers does influence the health of their children, this process is unlikely to be mediated by spermatozoal DNA methylation.
登录
查看更多内容
影响因子：
5.4
作者：
Danson AF;Marzi SJ;Lowe R;Holland ML;Rakyan VK
通讯作者：
Rakyan VK
影响因子：
5.8
作者：
Gorrie-Stone, Tyler J.;Smart, Melissa C.;Schalkwyk, Leonard C.
通讯作者：
Schalkwyk, Leonard C.
影响因子：
3.7
作者：
Hannon E;Lunnon K;Schalkwyk L;Mill J
通讯作者：
Mill J
影响因子：
25
作者：
Dias, Brian G.;Ressier, Kerry J.
通讯作者：
Ressier, Kerry J.
影响因子：
12.3
作者：
Horvath S
通讯作者：
Horvath S