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DNA甲基化破坏改变造血分化
作者:小柯机器人 发布时间:2020/3/29 23:37:40

美国纽约基因组中心Dan A. Landau研究组近日取得一项新成果,他们的最新工作表明,DNA甲基化的破坏改变了造血分化。2020年3月23日,国际知名学术期刊《自然—遗传学》在线发表了这一成果。

研究人员表示,DNA甲基化相关基因(DNAme;例如,TET2和DNMT3A)的突变经常在血液系统恶性肿瘤和克隆性造血过程中观察到。
 
通过将单细胞测序应用于小鼠造血干细胞和祖细胞,研究人员观察到这些突变破坏了造血细胞分化,导致Tet2或Dnmt3a缺失后红系和骨髓单核祖细胞的频率发生相反的变化。值得注意的是,这些变化可追溯到未分化造血干细胞中转录激活的改变。研究人员发现,结合基序中CpG富集的偏差导致了转录因子的差异敏感性。单细胞转录组分析表明,DNMT3A突变的人类克隆性造血系统骨髓祖细胞的转录活化存在相似的偏差。这些数据表明,DNAme塑造造血分化的表观图谱,并表明,全基因组甲基化改变通过转录因子结合基序的CpG偏差富集导致分化改变。
 
附:英文原文

Title: DNA methylation disruption reshapes the hematopoietic differentiation landscape

Author: Franco Izzo, Stanley C. Lee, Asaf Poran, Ronan Chaligne, Federico Gaiti, Baptiste Gross, Rekha R. Murali, Sunil D. Deochand, Chelston Ang, Philippa Wyndham Jones, Anna S. Nam, Kyu-Tae Kim, Steven Kothen-Hill, Rafael C. Schulman, Michelle Ki, Priscillia Lhoumaud, Jane A. Skok, Aaron D. Viny, Ross L. Levine, Ephraim Kenigsberg, Omar Abdel-Wahab, Dan A. Landau

Issue&Volume: 2020-03-23

Abstract: Mutations in genes involved in DNA methylation (DNAme; for example, TET2 and DNMT3A) are frequently observed in hematological malignancies1,2,3 and clonal hematopoiesis4,5. Applying single-cell sequencing to murine hematopoietic stem and progenitor cells, we observed that these mutations disrupt hematopoietic differentiation, causing opposite shifts in the frequencies of erythroid versus myelomonocytic progenitors following Tet2 or Dnmt3a loss. Notably, these shifts trace back to transcriptional priming skews in uncommitted hematopoietic stem cells. To reconcile genome-wide DNAme changes with specific erythroid versus myelomonocytic skews, we provide evidence in support of differential sensitivity of transcription factors due to biases in CpG enrichment in their binding motif. Single-cell transcriptomes with targeted genotyping showed similar skews in transcriptional priming of DNMT3A-mutated human clonal hematopoiesis bone marrow progenitors. These data show that DNAme shapes the topography of hematopoietic differentiation, and support a model in which genome-wide methylation changes are transduced to differentiation skews through biases in CpG enrichment of the transcription factor binding motif.

DOI: 10.1038/s41588-020-0595-4

Source: https://www.nature.com/articles/s41588-020-0595-4

期刊信息

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:25.455
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex