Drivers and sites of diversity in the DNA adenine methylomes of 93 Mycobacterium tuberculosis complex clinical isolates.
Drivers and sites of diversity in the DNA adenine methylomes of 93 Mycobacterium tuberculosis complex clinical isolates.
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93个结核分枝杆菌复合物临床分离株的DNA腺嘌呤甲基甲基组中多样性的驱动因素和部位。
DOI：
10.7554/elife.58542
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发表时间：
2020-10-27
期刊：
影响因子：
7.7
通讯作者：
Valafar F
中科院分区：
文献类型：
--
作者：
Modlin SJ;Conkle-Gutierrez D;Kim C;Mitchell SN;Morrissey C;Weinrick BC;Jacobs WR;Ramirez-Busby SM;Hoffner SE;Valafar F
这项研究从七个谱系中分离出93种分支机构的DNA腺嘌呤甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲酸的甲基甲基化合物（MTBC）与完全宣布的，从事的整合性基因组相结合。甲基转移酶的等位基因表明，细胞内随机甲基化在等源性培养物中产生甲基化的甲基化合物，我们将其形式化为“细胞间的镶嵌甲基化，IMM）在全球著名的Beijing Supertights and Indractions中，几乎是无处不在的。 ER HSDM甲基化直接影响转录。最后，比较和功能分析确定了351个位点在分离株之间可识别高变量，并且这种多摩变的相互作用揭示了临床分离株中甲基甲基变异性的特征，并为假设MTBC生理学和适应性进化的DNA腺苷化功能提供了合理的基础。
This study assembles DNA adenine methylomes for 93 Mycobacterium tuberculosis complex (MTBC) isolates from seven lineages paired with fully-annotated, finished, de novo assembled genomes. Integrative analysis yielded four key results. First, methyltransferase allele-methylome mapping corrected methyltransferase variant effects previously obscured by reference-based variant calling. Second, heterogeneity analysis of partially active methyltransferase alleles revealed that intracellular stochastic methylation generates a mosaic of methylomes within isogenic cultures, which we formalize as ‘intercellular mosaic methylation’ (IMM). Mutation-driven IMM was nearly ubiquitous in the globally prominent Beijing sublineage. Third, promoter methylation is widespread and associated with differential expression in the ΔhsdM transcriptome, suggesting promoter HsdM-methylation directly influences transcription. Finally, comparative and functional analyses identified 351 sites hypervariable across isolates and numerous putative regulatory interactions. This multi-omic integration revealed features of methylomic variability in clinical isolates and provides a rational basis for hypothesizing the functions of DNA adenine methylation in MTBC physiology and adaptive evolution.