SIRT1 affects DNA methylation of polycomb group protein target genes, a hotspot of the epigenetic shift observed in ageing.
SIRT1 affects DNA methylation of polycomb group protein target genes, a hotspot of the epigenetic shift observed in ageing.
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SIRT1影响Polycomb基团蛋白靶基因的DNA甲基化，这是衰老中观察到的表观遗传转移的热点。
DOI：
10.1186/s40246-015-0036-0
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发表时间：
2015-06-24
期刊：
影响因子：
4.5
通讯作者：
Ford D
中科院分区：
文献类型：
--
作者：
Wakeling LA;Ions LJ;Escolme SM;Cockell SJ;Su T;Dey M;Hampton EV;Jenkins G;Wainwright LJ;McKay JA;Ford D
SIRT1 可能在饮食限制引起的健康寿命延长中发挥作用。 SIRT1 的作用是多效性的，对健康寿命的影响可能包括对 DNA 甲基化的影响。多梳族蛋白靶基因 (PCGT) 受到干细胞中表观遗传机制的抑制，部分是通过多梳抑制复合物 (PRC) 的作用，并且之前已被证明与特别容易受到 DNA 甲基化年龄相关变化影响的位点相对应。我们假设 SIRT1 会影响 DNA 甲基化，特别是在 PCGT 上。为了绘制基因组中 SIRT1 影响 DNA 甲基化的位点，我们通过用表达构建体或 siRNA 瞬时转染来改变人肠道 (Caco-2) 和血管内皮 (HuVEC) 细胞中的 SIRT1 表达。 DNA 富集甲基化部分，然后进行测序 (HuVEC) 或与人启动子微阵列 (Caco-2) 杂交。 SIRT1 操作影响 DNA 甲基化的基因谱在两种细胞系中均富含 PCGT，从而支持了我们的假设。 SIRT1 敲低不会影响 7 个 PRC 成分的 mRNA，也不影响 DNMT1 或 DNMT3b。因此，我们没有发现任何证据表明 SIRT1 通过影响这些基因转录本的表达来影响 PCGT 的 DNA 甲基化。 EZH2 是 PRC2 的一个组成部分，可通过与 DNA 甲基转移酶 (DNMT) 结合影响 DNA 甲基化，它不与 SIRT1 共免疫沉淀，并且 SIRT1 敲低不影响 EZH2 蛋白的表达。因此，SIRT1 对 PCGT DNA 甲基化的影响不太可能是通过与 EZH2 的直接分子间关联或通过影响其表达来介导的。 SIRT1 影响整个基因组的 DNA 甲基化，尤其是 PCGT。尽管 SIRT1 发挥这些作用的机制尚未揭晓，但这种作用可能有助于延长健康寿命，例如在饮食限制的情况下。本文的在线版本 (doi:10.1186/s40246-015-0036-0) 包含补充材料，可供授权用户使用。
SIRT1 is likely to play a role in the extension in healthspan induced by dietary restriction. Actions of SIRT1 are pleiotropic, and effects on healthspan may include effects on DNA methylation. Polycomb group protein target genes (PCGTs) are suppressed by epigenetic mechanisms in stem cells, partly through the actions of the polycomb repressive complexes (PRCs), and have been shown previously to correspond with loci particularly susceptible to age-related changes in DNA methylation. We hypothesised that SIRT1 would affect DNA methylation particularly at PCGTs. To map the sites in the genome where SIRT1 affects DNA methylation, we altered SIRT1 expression in human intestinal (Caco-2) and vascular endothelial (HuVEC) cells by transient transfection with an expression construct or with siRNA. DNA was enriched for the methylated fraction then sequenced (HuVEC) or hybridised to a human promoter microarray (Caco-2). The profile of genes where SIRT1 manipulation affected DNA methylation was enriched for PCGTs in both cell lines, thus supporting our hypothesis. SIRT1 knockdown affected the mRNA for none of seven PRC components nor for DNMT1 or DNMT3b. We thus find no evidence that SIRT1 affects DNA methylation at PCGTs by affecting the expression of these gene transcripts. EZH2, a component of PRC2 that can affect DNA methylation through association with DNA methyltransferases (DNMTs), did not co-immunoprecipitate with SIRT1, and SIRT1 knockdown did not affect the expression of EZH2 protein. Thus, it is unlikely that the effects of SIRT1 on DNA methylation at PCGTs are mediated through direct intermolecular association with EZH2 or through effects in its expression. SIRT1 affects DNA methylation across the genome, but particularly at PCGTs. Although the mechanism through which SIRT1 has these effects is yet to be uncovered, this action is likely to contribute to extended healthspan, for example under conditions of dietary restriction. The online version of this article (doi:10.1186/s40246-015-0036-0) contains supplementary material, which is available to authorized users.
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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：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
64.8
作者：
Burnett, Camilla;Valentini, Sara;Cabreiro, Filipe;Goss, Martin;Somogyvari, Milan;Piper, Matthew D.;Hoddinott, Matthew;Sutphin, George L.;Leko, Vid;McElwee, Joshua J.;Vazquez-Manrique, Rafael P.;Orfila, Anne-Marie;Ackerman, Daniel;Au, Catherine;Vinti, Giovanna;Riesen, Michele;Howard, Ken;Neri, Christian;Bedalov, Antonio;Kaeberlein, Matt;Soti, Csaba;Partridge, Linda;Gems, David
通讯作者：
Gems, David
影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
DOI：
10.1073/pnas.0409875102
发表时间：
2005-02-08
影响因子：
11.1
作者：
Kuzmichev, A;Margueron, R;Reinberg, D
通讯作者：
Reinberg, D