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首页> 外文期刊>Molecular and Cellular Biology >DOT1L-Mediated H3K79 Methylation in Chromatin Is Dispensable for Wnt Pathway-Specific and Other Intestinal Epithelial Functions
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DOT1L-Mediated H3K79 Methylation in Chromatin Is Dispensable for Wnt Pathway-Specific and Other Intestinal Epithelial Functions

机译：染色质中DOT1L介导的H3K79甲基化对于Wnt途径特异性和其他肠上皮功能是必不可少的

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Methylation of H3K79 is associated with chromatin at expressed genes, though it is unclear if this histone modification is required for transcription of all genes. Recent studies suggest that Wnt-responsive genes depend particularly on H3K79 methylation, which is catalyzed by the methyltransferase DOT1L. Human leukemias carrying MLL gene rearrangements show DOT1L-mediated H3K79 methylation and aberrant expression of leukemogenic genes. DOT1L inhibitors reverse these effects, but their clinical use is potentially limited by toxicity in Wnt-dependent tissues such as intestinal epithelium. Genome-wide positioning of the H3K79me2 mark in Lgr5+ mouse intestinal stem cells and mature intestinal villus epithelium correlated with expression levels of all transcripts and not with Wnt-responsive genes per se. Selective Dot1l disruption in Lgr5+ stem cells or in whole intestinal epithelium eliminated H3K79me2 from the respective compartments, allowing genetic evaluation of DOT1L requirements. The absence of methylated H3K79 did not impair health, intestinal homeostasis, or expression of Wnt target genes in crypt epithelium for up to 4 months, despite increased crypt cell apoptosis. Global transcript profiles in Dot1l-null cells were barely altered. Thus, H3K79 methylation is not essential for transcription of Wnt-responsive or other intestinal genes, and intestinal toxicity is not imperative when DOT1L is rendered inactive in vivo.
机译：H3K79的甲基化与表达基因的染色质有关，尽管尚不清楚是否需要对所有基因转录进行组蛋白修饰。最近的研究表明，Wnt反应基因特别依赖于H3K79甲基化，这是由甲基转移酶DOT1L催化的。携带 MLL 基因重排的人类白血病显示DOT1L介导的H3K79甲基化和致白血病基因的异常表达。 DOT1L抑制剂可逆转这些作用，但其临床应用可能受到Wnt依赖性组织（如肠上皮）中毒性的限制。 H3K79me2标记在Lgr5 + 小鼠肠道干细胞和成熟的肠绒毛上皮细胞中的全基因组定位与所有转录本的表达水平相关，而与Wnt应答基因本身无关。 Lgr5 + 干细胞或整个肠上皮细胞中的选择性 Dot11l 破坏消除了各个区室中的H3K79me2，从而可以进行DOT1L需求的遗传评估。尽管隐窝细胞凋亡增加，但甲基化H3K79的缺失最多4个月都不会损害其健康，肠道稳态或隐窝上皮中Wnt目标基因的表达。在 Dot11 -无效细胞中的全局转录谱几乎没有改变。因此，H3K79甲基化对于Wnt反应性或其他肠道基因的转录不是必需的，并且当DOT1L在体内变为非活性时，肠毒性不是必须的。

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