Department of Molecular, Cell, and Developmental Biology, University of California Santa Cruz, Santa Cruz, California, United States of America.
PLoS Genet. 2010 Sep 2;6(9):e1001091. doi: 10.1371/journal.pgen.1001091.
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 approximately 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.
真核生物中组蛋白 H3K36 的甲基化是由多个甲基转移酶介导的。与 RNA 聚合酶 II 相关的 Set2 相关 H3K36 甲基转移酶通过与 RNA 聚合酶 II 相关联而靶向基因，并参与防止基因体内异常转录起始。哺乳动物 NSD 家族的 H3K36 甲基转移酶的靶向作用和作用尚不清楚，已知它们参与人类发育障碍和肿瘤发生。我们使用全基因组染色质免疫沉淀 (ChIP) 来研究 Caenorhabditis elegans NSD 同源物 MES-4 的靶向作用和作用，MES-4 被母体提供给后代，并需要新生生殖细胞的存活。在早期 C. elegans 胚胎中的 ChIP 分析表明，与免疫染色结果一致，MES-4 结合位点集中在常染色体和 X 染色体的最左侧约 2%（300kb）。MES-4 覆盖大约 5000 个基因的编码区域，基因体的 5' 区域略有升高。尽管 MES-4 通常位于 Pol II 结合基因上，但对具有不同时空表达模式的基因集的分析表明，Pol II 与基因的关联既不是必需的，也不是充分的，以招募 MES-4。在早期胚胎中，MES-4 与先前在母体生殖系中表达的基因相关联，这种相互作用不需要 Pol II 与这些基因座持续关联。相反，Pol II 与在胚胎中新表达的基因的关联不会导致 MES-4 招募到这些基因。这些和其他发现表明，MES-4 （也许还有相关的哺乳动物 NSD 蛋白）为 H3K36 甲基化提供了一种新颖的表观遗传功能，可能与正在进行的转录无关。我们提出 MES-4 将亲本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 PGC 执行适当的生殖系程序至关重要。
