KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands.
KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands.
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DOI：
10.7554/elife.00205
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发表时间：
2012-12-18
期刊：
影响因子：
7.7
通讯作者：
Klose RJ
中科院分区：
文献类型：
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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
CpG岛(CGI)与大多数哺乳动物基因启动子相关。CGI的一个子集作为多梳反应元件(Pres)，被多梳沉默系统识别，以调节参与早期发育的基因的表达。CGI是如何作为多梳抑制复合体的成核中心发挥作用的尚不清楚。在这里，我们发现Kdm2b(Fbxl10)特异性识别CGI中的非甲基化DNA，并招募多梳抑制复合体1(PRC1)。这有助于组蛋白H_2A赖氨酸119泛素化(H_2AK119ub1)和基因抑制。出人意料的是，我们还发现CGI被整个基因组中低水平的PRC1占据，这表明Kdm2b-PRC1复合体可能会采样CGI相关基因，从而对多梳介导的沉默易感性。这些观察结果表明，Kdm2b对CGI的识别与针对多梳抑制系统之间存在意想不到的直接联系。这为一个新的模型提供了基础，该模型将CGI的功能描述为哺乳动物的PreS。DOI：真核细胞中的http://dx.doi.org/10.7554/eLife.00205.001基因表达可以通过许多不同的方式进行控制，包括各种表观遗传机制，这些机制不涉及对定义基因本身的DNA序列进行改变。脊椎动物基因沉默的一个众所周知的表观遗传学机制是DNA甲基化-在胞嘧啶上添加一个甲基(CH3)，胞嘧啶是DNA中发现的四个碱基之一。甲基化被认为通过阻止转录因子与DNA结合来沉默基因，也通过招募抑制DNA转录的蛋白质来沉默基因。DNA甲基化在整个基因组中自然发生，主要发生在胞嘧啶与鸟嘌呤结合形成CpG二核苷酸的位置。虽然大多数CpG二核苷酸中的胞嘧啶碱基是甲基化的，但也有一小段DNA被称为CpG岛，其中包含高比例的未甲基化CpG二核苷酸。这些岛含有大量的胞嘧啶和鸟嘌呤碱基，它们经常在转录起始点或附近发现。长期以来，CpG岛上缺乏甲基化一直被认为在基因表达中具有被动作用，使得DNA很容易获得，并可供转录因子结合和启动转录。然而，最近的研究表明，CpG岛可能起到更积极的作用。特别是，研究表明，特定的蛋白质与CpG岛结合，可以创造更有利于基因表达的染色质环境。此外，CpG岛的一个子集还可以结合多梳蛋白，包括使基因表达沉默的多梳抑制复合体1(PRC1)。这些复合体在动物早期发育的基因调控中发挥了重要作用，但PRC1识别哺乳动物CpG岛的机制仍然是个谜。Farcas等人。现在揭示了一种名为Kdm2b(Fbxl10)的蛋白质可以识别CpG岛并向其中招募Prc1。为了实现这一点，Kdm2b编码了一个DNA结合域，该结构域专门识别非甲基化的CpG二核苷酸。Kdm2b通过与一个变异的Prc1复合体进行生化相互作用，然后在CpG岛上使Prc1成核，而Prc1的活性则沉默了胚胎干细胞中的某些多梳靶基因。令人惊讶的是，Farcas等人。此外，在全基因组范围内的大多数CpG岛上也发现了低水平但可察觉的Prc1水平，此外，在选定的岛上还发现了高水平的Prc1：这表明Kdm2b可能会对整个基因组进行采样，以找到可以建立沉默的CpG岛。对多梳抑制系统以及CpG岛在其中的作用的更好的理解，可能会导致对表观遗传机制在哺乳动物发育中的作用的新的见解。DOI：http://dx.doi.org/10.7554/eLife.00205.002
CpG islands (CGIs) are associated with most mammalian gene promoters. A subset of CGIs act as polycomb response elements (PREs) and are recognized by the polycomb silencing systems to regulate expression of genes involved in early development. How CGIs function mechanistically as nucleation sites for polycomb repressive complexes remains unknown. Here we discover that KDM2B (FBXL10) specifically recognizes non-methylated DNA in CGIs and recruits the polycomb repressive complex 1 (PRC1). This contributes to histone H2A lysine 119 ubiquitylation (H2AK119ub1) and gene repression. Unexpectedly, we also find that CGIs are occupied by low levels of PRC1 throughout the genome, suggesting that the KDM2B-PRC1 complex may sample CGI-associated genes for susceptibility to polycomb-mediated silencing. These observations demonstrate an unexpected and direct link between recognition of CGIs by KDM2B and targeting of the polycomb repressive system. This provides the basis for a new model describing the functionality of CGIs as mammalian PREs. DOI: http://dx.doi.org/10.7554/eLife.00205.001 Gene expression in eukaryotic cells can be controlled in a number of different ways, including various epigenetic mechanisms that do not involve making changes to DNA sequences that define the genes themselves. A well-known epigenetic mechanism for silencing genes in vertebrates is DNA methylation—the addition of a methyl group (CH3) to cytosine, which is one of the four bases found in the DNA. Methylation is thought to silence genes by preventing transcription factors from binding to the DNA, and also by recruiting proteins that inhibit the transcription of DNA. DNA methylation occurs naturally throughout the genome, mostly at positions where cytosine is bonded to guanine to form a CpG dinucleotide. While the cytosine bases in most CpG dinucleotides are methylated, there are short stretches of DNA known as CpG islands that contain a high proportion of unmethylated CpG dinucleotides. These islands contain a large number of cytosine and guanine bases, and they are often found at or near transcription start sites. The lack of methylation at CpG islands has long been assumed to have a passive role in gene expression, leaving the DNA easily accessible and available for transcription factors to bind and initiate transcription. However, recent work suggests that CpG islands may have a more active role. In particular, it has been shown that specific proteins bind to CpG islands to create chromatin environments that are more favourable for the initiation of gene expression. Moreover, a subset of CpG islands can also bind polycomb-group proteins, including the polycomb repressive complex 1 (PRC1) that silence gene expression. These complexes have an important role in the regulation of genes during early development in animals, but the mechanism by which PRC1 recognizes CpG islands in mammals has remained enigmatic. Farcas et al. now reveal that a protein, KDM2B (FBXL10), can recognize CpG islands and recruit PRC1 to them. To achieve this, KDM2B encodes a DNA binding domain that specifically recognizes non-methylated CpG dinucleotides. By interacting biochemically with a variant PRC1 complex, KDM2B then nucleates PRC1 at CpG islands, and PRC1 activity silences certain polycomb target genes in embryonic stem cells. Surprisingly, Farcas et al. also find low but appreciable levels of PRC1 at most CpG islands genome-wide, in addition to the high levels of PRC1 at selected islands: this suggests that KDM2B may sample the whole genome to find CpG islands where PRC1 can establish silencing. An improved understanding of the polycomb repressive system, and the role of CpG islands within it, could lead to new insights into the role of epigenetic mechanisms in mammalian development. DOI: http://dx.doi.org/10.7554/eLife.00205.002