Region-based epigenetic clock design improves RRBS-based age prediction.
Region-based epigenetic clock design improves RRBS-based age prediction.
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DOI：
10.1111/acel.13866
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发表时间：
2023-08
期刊：
影响因子：
7.8
通讯作者：
Chandra, Tamir
中科院分区：
文献类型：
--
作者：
Simpson, Daniel J. J.;Zhao, Qian;Olova, Nelly N. N.;Dabrowski, Jan;Xie, Xiaoxiao;Latorre-Crespo, Eric;Chandra, Tamir
最近的研究表明，表观遗传再生可以使用模拟卡路里限制的药物和重新编程诱导的再生等技术来实现。为了有效地测试体内的返老还童，小鼠模型是最安全的替代方案。然而，我们发现，最近为小鼠简化表示亚硫酸盐测序(RRBS)数据开发的表观遗传学时钟在应用于外部数据集时性能明显较差。我们表明，年龄预测所需的站点和关键CPG的覆盖率在数据集之间差异很大，这可能是RRBS时钟缺乏可转移性的原因之一。为了缓解基于RRBS的年龄预测中的覆盖问题，我们提出了两种新的设计策略，它们使用大区域的平均甲基化而不是单个CPG，其中区域由滑动窗口(例如5 kb)定义，或者CPG的基于密度的聚类。我们观察到，与已发表的基于个体CpG的技术相比，当应用于外部数据集时，我们的区域血时钟(RegBC)的相关性和误差都有所改善。当应用于低覆盖率数据并在接受卡路里限制的小鼠中检测到负年龄加速时，RegBCs也更健壮。我们的RegBC提供了一个原则证据，即可以通过考虑一个区域上的多个CPG来改善RRBS数据集的年龄预测，这否定了目前阻碍基于单个CPG的方法的读取深度的缺乏。为了在活体模型生物上有效地测试复壮技术，我们开发了两种新的设计策略，它们使用区域平均甲基化，而不是单个CPG(我们证明这种方法在应用于外部测试数据集时是无效的)。区域由滑动窗口(例如，5 kb)或基于密度的CPG聚类来定义。我们观察到，在卡路里限制的小鼠中，我们的区域血钟(RegBC)的相关性和误差得到了改善，对低覆盖率数据的稳健性增强，以及负年龄加速。
Recent studies suggest that epigenetic rejuvenation can be achieved using drugs that mimic calorie restriction and techniques such as reprogramming‐induced rejuvenation. To effectively test rejuvenation in vivo, mouse models are the safest alternative. However, we have found that the recent epigenetic clocks developed for mouse reduced‐representation bisulphite sequencing (RRBS) data have significantly poor performance when applied to external datasets. We show that the sites captured and the coverage of key CpGs required for age prediction vary greatly between datasets, which likely contributes to the lack of transferability in RRBS clocks. To mitigate these coverage issues in RRBS‐based age prediction, we present two novel design strategies that use average methylation over large regions rather than individual CpGs, whereby regions are defined by sliding windows (e.g. 5 kb), or density‐based clustering of CpGs. We observe improved correlation and error in our regional blood clocks (RegBCs) compared to published individual‐CpG‐based techniques when applied to external datasets. The RegBCs are also more robust when applied to low coverage data and detect a negative age acceleration in mice undergoing calorie restriction. Our RegBCs offer a proof of principle that age prediction of RRBS datasets can be improved by accounting for multiple CpGs over a region, which negates the lack of read depth currently hindering individual‐CpG‐based approaches. To effectively test rejuvenation techniques on in vivo model organisms, we have developed two novel design strategies that use mean methylation over regions, rather than individual CpGs (an approach which we show is ineffective when applied to external test datasets). Regions are defined by sliding windows (e.g. 5 kb), or density‐based clustering of CpGs. We observe improved correlation and error in our regional blood clocks (RegBCs), increased robustness on low coverage data and negative age acceleration in calorie‐restricted mice.
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影响因子：
4.5
作者：
Christensen BC;Houseman EA;Marsit CJ;Zheng S;Wrensch MR;Wiemels JL;Nelson HH;Karagas MR;Padbury JF;Bueno R;Sugarbaker DJ;Yeh RF;Wiencke JK;Kelsey KT
通讯作者：
Kelsey KT
影响因子：
3.7
作者：
Bocklandt S;Lin W;Sehl ME;Sánchez FJ;Sinsheimer JS;Horvath S;Vilain E
通讯作者：
Vilain E
全基因组甲基化谱揭示了人类衰老速度的定量观点。
影响因子：
16
作者：
Hannum, Gregory;Guinney, Justin;Zhao, Ling;Zhang, Li;Hughes, Guy;Sadda, SriniVas;Klotzle, Brandy;Bibikova, Marina;Fan, Jian-Bing;Gao, Yuan;Deconde, Rob;Chen, Menzies;Rajapakse, Indika;Friend, Stephen;Ideker, Trey;Zhang, Kang
通讯作者：
Zhang, Kang
影响因子：
7.8
作者：
Fiorito G;Caini S;Palli D;Bendinelli B;Saieva C;Ermini I;Valentini V;Assedi M;Rizzolo P;Ambrogetti D;Ottini L;Masala G
通讯作者：
Masala G
哺乳动物甲基化阵列，用于在保守序列上分析甲基化水平。
影响因子：
16.6
作者：
Arneson A;Haghani A;Thompson MJ;Pellegrini M;Kwon SB;Vu H;Maciejewski E;Yao M;Li CZ;Lu AT;Morselli M;Rubbi L;Barnes B;Hansen KD;Zhou W;Breeze CE;Ernst J;Horvath S
通讯作者：
Horvath S