Protection of CpG islands from DNA methylation is DNA-encoded and evolutionarily conserved.
Protection of CpG islands from DNA methylation is DNA-encoded and evolutionarily conserved.
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DOI：
10.1093/nar/gkw258
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发表时间：
2016-08-19
影响因子：
14.9
通讯作者：
Klose RJ
中科院分区：
文献类型：
--
作者：
Long HK;King HW;Patient RK;Odom DT;Klose RJ
DNA甲基化是一种覆盖脊椎动物基因组的抑制表观遗传修饰。被称为CpG岛（cgi）的区域是DNA甲基化的顽固性区域，通常与基因启动子相关，在基因调控中起核心作用。然而，在正常的基因组背景下，cgi是如何逃避DNA甲基化机制的，以及这些机制是否在进化上是保守的，仍然是一个谜。为了解决这些基本问题，我们利用了一个跨染色体动物模型和基因组方法来了解体内低甲基化状态是如何形成的，并发现控制CGI形成的机制是否具有进化保守性。引人注目的是，将人类染色体插入小鼠体内发现，无论宿主物种如何，启动子相关的cgi都难以发生DNA甲基化，这表明DNA序列通过进化保守机制在指定低甲基化状态中起着核心作用。相比之下，基因启动子远端的元件在宿主物种之间表现出更多的甲基化变化，揭示了在塑造远离基因启动子的DNA甲基化景观时对核苷酸频率和DNA结合转录因子的占用的广泛依赖。年轻的富含CpG的谱系限制性重复序列在缺乏针对这些序列的甲基化的共同进化机制的情况下避免了DNA甲基化，以及物种特异性DNA结合事件保护CpG贫乏区域的DNA甲基化。最后，将小鼠染色体片段移植到进化距离较远的斑马鱼中，揭示了一种机制保守和dna编码逻辑的存在，这种逻辑决定了脊椎动物物种之间CGI的形成。
DNA methylation is a repressive epigenetic modification that covers vertebrate genomes. Regions known as CpG islands (CGIs), which are refractory to DNA methylation, are often associated with gene promoters and play central roles in gene regulation. Yet how CGIs in their normal genomic context evade the DNA methylation machinery and whether these mechanisms are evolutionarily conserved remains enigmatic. To address these fundamental questions we exploited a transchromosomic animal model and genomic approaches to understand how the hypomethylated state is formed in vivo and to discover whether mechanisms governing CGI formation are evolutionarily conserved. Strikingly, insertion of a human chromosome into mouse revealed that promoter-associated CGIs are refractory to DNA methylation regardless of host species, demonstrating that DNA sequence plays a central role in specifying the hypomethylated state through evolutionarily conserved mechanisms. In contrast, elements distal to gene promoters exhibited more variable methylation between host species, uncovering a widespread dependence on nucleotide frequency and occupancy of DNA-binding transcription factors in shaping the DNA methylation landscape away from gene promoters. This was exemplified by young CpG rich lineage-restricted repeat sequences that evaded DNA methylation in the absence of co-evolved mechanisms targeting methylation to these sequences, and species specific DNA binding events that protected against DNA methylation in CpG poor regions. Finally, transplantation of mouse chromosomal fragments into the evolutionarily distant zebrafish uncovered the existence of a mechanistically conserved and DNA-encoded logic which shapes CGI formation across vertebrate species.
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影响因子：
--
作者：
Anand M;Prasad BV
通讯作者：
Prasad BV
影响因子：
16
作者：
Blackledge NP;Zhou JC;Tolstorukov MY;Farcas AM;Park PJ;Klose RJ
通讯作者：
Klose RJ
影响因子：
7.7
作者：
Farcas AM;Blackledge NP;Sudbery I;Long HK;McGouran JF;Rose NR;Lee S;Sims D;Cerase A;Sheahan TW;Koseki H;Brockdorff N;Ponting CP;Kessler BM;Klose RJ
通讯作者：
Klose RJ
影响因子：
4
作者：
Hancks, Dustin C.;Kazazian, Haig H., Jr.
通讯作者：
Kazazian, Haig H., Jr.
影响因子：
10.5
作者：
Aravin, Alexei A.;Bourc'his, Deborah
通讯作者：
Bourc'his, Deborah