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单细胞多组学分析揭示混合表型急性白血病调控程序
2019-12-03 11:54

美国斯坦福大学医学院William J. Greenleaf、Sandy Klemm、Lisa M. McGinnis等研究人员合作利用单细胞多组学分析,鉴定了混合表型急性白血病的调控程序。2019年12月2日,《自然—生物技术》在线发表了这项成果。

研究人员提出了一个单细胞框架,其整合了多路复用的蛋白质定量、转录组分析和染色质可及性分析。使用这种方法,研究人员建立了健康血液发育的正常表观遗传基线,然后将其用于消除混合表型急性白血病患者血液中异常分子特征的卷积。尽管在患者队列中存在广泛的表观遗传异质性,但研究人员观察到了患者之间常见的恶性特征以及个体患者表型间共有的患者特异性调节特征。转录组和染色质可及性图的综合分析确定了91601个潜在的peak-to-gene连锁和调控白血病特异性基因的转录因子,例如与标记基因CD69邻近的RUNX1连锁调控元件。这些结果表明,在正常发育的框架内对单个细胞进行综合、多组学分析可以揭示来自患者样品的疾病的独特和共享分子机制。

据介绍,鉴定人类疾病的原因,就需要对涉及DNA可及性、基因表达和蛋白质丰度的异常分子表型进行反卷积分析。

附:英文原文

Title: Single-cell multiomic analysis identifies regulatory programs in mixed-phenotype acute leukemia

Author: Jeffrey M. Granja, Sandy Klemm, Lisa M. McGinnis, Arwa S. Kathiria, Anja Mezger, M. Ryan Corces, Benjamin Parks, Eric Gars, Michaela Liedtke, Grace X. Y. Zheng, Howard Y. Chang, Ravindra Majeti, William J. Greenleaf

Issue&Volume: 2019-12-02

Abstract: Identifying the causes of human diseases requires deconvolution of abnormal molecular phenotypes spanning DNA accessibility, gene expression and protein abundance1,2,3. We present a single-cell framework that integrates highly multiplexed protein quantification, transcriptome profiling and analysis of chromatin accessibility. Using this approach, we establish a normal epigenetic baseline for healthy blood development, which we then use to deconvolve aberrant molecular features within blood from patients with mixed-phenotype acute leukemia4,5. Despite widespread epigenetic heterogeneity within the patient cohort, we observe common malignant signatures across patients as well as patient-specific regulatory features that are shared across phenotypic compartments of individual patients. Integrative analysis of transcriptomic and chromatin-accessibility maps identified 91,601 putative peak-to-gene linkages and transcription factors that regulate leukemia-specific genes, such as RUNX1-linked regulatory elements proximal to the marker gene CD69. These results demonstrate how integrative, multiomic analysis of single cells within the framework of normal development can reveal both distinct and shared molecular mechanisms of disease from patient samples.

DOI: 10.1038/s41587-019-0332-7

Source: https://www.nature.com/articles/s41587-019-0332-7

Nature Biotechnology:《自然—生物技术》,创刊于1996年。隶属于施普林格·自然出版集团,最新IF:68.164
官方网址:https://www.nature.com/nbt/
投稿链接:https://mts-nbt.nature.com/cgi-bin/main.plex


本期文章:《自然—生物技术》:Online/在线发表

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