小柯机器人

美国纽约基因组中心Dan A. Landau和美国Dana-Farber癌症研究所Irene Ghobrial共同合作，近期取得重要工作进展。他们通过研究人类克隆造血的单细胞多组学，揭示了DNMT3A R882突变通过选择性低甲基化扰乱早期祖细胞状态。相关研究成果2022年9月22日在线发表于《自然—遗传学》杂志上。

由于突变和野生型细胞混合在一起，研究人员很难将基因型与表型联系起来。为了克服这一限制，研究人员利用多模态单细胞测序，捕获DNMT3A R882突变克隆造血个体的祖细胞的基因型、转录组和甲基化组。DNMT3A突变导致髓系偏向于淋巴系，以及未成熟髓系祖细胞的扩增，这些祖细胞向巨核细胞-红系的命运做好准备，谱系和白血病干细胞标志物的表达失调。突变的DNMT3A导致多梳抑制复合物2靶标和特定CpG侧翼基序的优先低甲基化。

值得注意的是，低甲基化基序富含关键造血转录因子的结合基序，作为DNMT3A突变和异常转录表型之间的潜在机制联系。因此，单细胞多组学为定义驱动克隆嵌合突变的下游结果铺平了道路。

据介绍，在健康人体组织的克隆扩增中，包括克隆造血中，已经检测到癌症基因的体细胞突变。

附：英文原文

Title: Single-cell multi-omics of human clonal hematopoiesis reveals that DNMT3A R882 mutations perturb early progenitor states through selective hypomethylation

Author: Nam, Anna S., Dusaj, Neville, Izzo, Franco, Murali, Rekha, Myers, Robert M., Mouhieddine, Tarek H., Sotelo, Jesus, Benbarche, Salima, Waarts, Michael, Gaiti, Federico, Tahri, Sabrin, Levine, Ross, Abdel-Wahab, Omar, Godley, Lucy A., Chaligne, Ronan, Ghobrial, Irene, Landau, Dan A.

Issue&Volume: 2022-09-22

Abstract: Somatic mutations in cancer genes have been detected in clonal expansions across healthy human tissue, including in clonal hematopoiesis. However, because mutated and wild-type cells are admixed, we have limited ability to link genotypes with phenotypes. To overcome this limitation, we leveraged multi-modality single-cell sequencing, capturing genotype, transcriptomes and methylomes in progenitors from individuals with DNMT3A R882 mutated clonal hematopoiesis. DNMT3A mutations result in myeloid over lymphoid bias, and an expansion of immature myeloid progenitors primed toward megakaryocytic–erythroid fate, with dysregulated expression of lineage and leukemia stem cell markers. Mutated DNMT3A leads to preferential hypomethylation of polycomb repressive complex 2 targets and a specific CpG flanking motif. Notably, the hypomethylation motif is enriched in binding motifs of key hematopoietic transcription factors, serving as a potential mechanistic link between DNMT3A mutations and aberrant transcriptional phenotypes. Thus, single-cell multi-omics paves the road to defining the downstream consequences of mutations that drive clonal mosaicism.

DOI: 10.1038/s41588-022-01179-9

Source: https://www.nature.com/articles/s41588-022-01179-9

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
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