The histone H3K36 methyltransferase MES-4 acts epigenetically to transmit the memory of germline gene expression to progeny.
The histone H3K36 methyltransferase MES-4 acts epigenetically to transmit the memory of germline gene expression to progeny.
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DOI：
10.1371/journal.pgen.1001091
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发表时间：
2010-09-02
期刊：
影响因子：
4.5
通讯作者：
Strome S
中科院分区：
文献类型：
--
作者：
Rechtsteiner A;Ercan S;Takasaki T;Phippen TM;Egelhofer TA;Wang W;Kimura H;Lieb JD;Strome S
在高等真核生物中，组蛋白H3K36的甲基化由多种甲基转移酶介导。Set2相关的H3K36甲基转移酶通过与RNA聚合酶II结合而靶向基因，并参与防止基因体内异常的转录起始。已知与人类发育障碍和肿瘤发生有关的哺乳动物H3K36甲基转移酶NSD家族的靶向作用和功能尚不清楚。我们利用全基因组染色质免疫沉淀（ChIP）来研究秀丽隐杆线虫NSD同源物MES - 4的靶向作用和功能，MES - 4由母体提供给后代，是新生生殖细胞存活所必需的。对早期秀丽隐杆线虫胚胎的ChIP分析显示，与免疫染色结果一致，MES - 4结合位点集中在常染色体和X染色体最左端约2%（300kb）的区域。MES - 4覆盖约5000个基因的编码区域，在基因体的5′区域有适度升高。尽管MES - 4通常存在于与Pol II结合的基因上，但对具有不同时空表达模式的基因集的分析表明，Pol II与基因的结合对于招募MES - 4既不是必需的，也不是充分的。在早期胚胎中，MES - 4与先前在母本生殖系中表达的基因相关联，这种相互作用不需要Pol II与这些位点持续结合。相反，Pol II与胚胎中新表达的基因结合不会导致MES - 4被招募到这些基因上。这些以及其他发现表明，MES - 4，或许还有相关的哺乳动物NSD蛋白，为H3K36甲基化提供了一种新的表观遗传功能，并且可能与正在进行的转录无关。我们提出，MES - 4将亲代生殖系中基因表达的记忆传递给后代，并且这种记忆作用对于原始生殖细胞执行正确的生殖系程序至关重要。
生殖细胞将基因组从一代传递到下一代。生殖细胞的特性和永生性对于物种的延续至关重要，然而调节这些特性的机制仍然难以捉摸。在秀丽隐杆线虫中，一种组蛋白甲基转移酶MES - 4是原始生殖细胞存活所必需的。MES - 4使组蛋白H3的赖氨酸36（H3K36）甲基化，这种修饰先前与转录延伸有关，并参与防止基因体内异常的转录起始。令人惊讶的是，我们对秀丽隐杆线虫胚胎中MES - 4结合位点的全基因组分析显示，MES - 4能够与在亲代线虫生殖系中表达但在胚胎中不再活跃转录的基因相关联。据我们所知，这是转录不偶联的H3K36甲基化的第一个例子。我们认为，MES - 4产生的H3K36甲基化通过标记生殖系表达的基因以及将基因表达的记忆从一代生殖细胞传递到下一代，起到一种“表观遗传作用”。
Methylation of histone H3K36 in higher eukaryotes is mediated by multiple methyltransferases. Set2-related H3K36 methyltransferases are targeted to genes by association with RNA Polymerase II and are involved in preventing aberrant transcription initiation within the body of genes. The targeting and roles of the NSD family of mammalian H3K36 methyltransferases, known to be involved in human developmental disorders and oncogenesis, are not known. We used genome-wide chromatin immunoprecipitation (ChIP) to investigate the targeting and roles of the Caenorhabditis elegans NSD homolog MES-4, which is maternally provided to progeny and is required for the survival of nascent germ cells. ChIP analysis in early C. elegans embryos revealed that, consistent with immunostaining results, MES-4 binding sites are concentrated on the autosomes and the leftmost ∼2% (300 kb) of the X chromosome. MES-4 overlies the coding regions of approximately 5,000 genes, with a modest elevation in the 5′ regions of gene bodies. Although MES-4 is generally found over Pol II-bound genes, analysis of gene sets with different temporal-spatial patterns of expression revealed that Pol II association with genes is neither necessary nor sufficient to recruit MES-4. In early embryos, MES-4 associates with genes that were previously expressed in the maternal germ line, an interaction that does not require continued association of Pol II with those loci. Conversely, Pol II association with genes newly expressed in embryos does not lead to recruitment of MES-4 to those genes. These and other findings suggest that MES-4, and perhaps the related mammalian NSD proteins, provide an epigenetic function for H3K36 methylation that is novel and likely to be unrelated to ongoing transcription. We propose that MES-4 transmits the memory of gene expression in the parental germ line to offspring and that this memory role is critical for the PGCs to execute a proper germline program. Germ cells transmit the genome from one generation to the next. The identity and immortality of germ cells are crucial for the perpetuation of species, yet the mechanisms that regulate these properties remain elusive. In C.elegans, a histone methyltransferase MES-4 is required for survival of the primordial germ cells. MES-4 methylates histone H3 at lysine 36 (H3K36), a modification previously linked to transcription elongation and involved in preventing aberrant transcription initiation within the body of genes. Surprisingly, our genome-wide analysis of MES-4 binding sites in C. elegans embryos revealed that MES-4 is capable of associating with genes that were expressed in the germ line of the parent worms but are no longer being actively transcribed in embryos. To our knowledge, this is the first example of transcription-uncoupled H3K36 methylation. We suggest that MES-4-generated H3K36 methylation serves an “epigenetic role,” by marking germline-expressed genes and by carrying the memory of gene expression from one generation of germ cells to the next.
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