Single-cell lineage tracing by endogenous mutations enriched in transposase accessible mitochondrial DNA
- Stanford University, United States
Abstract
Simultaneous measurement of cell lineage and cell fates is a longstanding goal in biomedicine. Here we describe EMBLEM, a strategy to track cell lineage using endogenous mitochondrial DNA variants in ATAC-seq data. We show that somatic mutations in mitochondrial DNA can reconstruct cell lineage relationships at single cell resolution with high sensitivity and specificity. Using EMBLEM, we define the genetic and epigenomic clonal evolution of hematopoietic stem cells and their progenies in patients with acute myeloid leukemia. EMBLEM extends lineage tracing to any eukaryotic organism without genetic engineering.
Data availability
Sequencing data have been deposited in GEO under accession codes GSE122576 and GSE122577.
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Single cell lineage tracing by endogenous mitochondrial DNA mutations in ATAC-seq dataNCBI Gene Expression Omnibus, GSE122576.
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Single cell lineage tracing by endogenous mitochondrial DNA mutations in ATAC-seq dataNCBI Gene Expression Omnibus, GSE122577.
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Single-cell chromatin accessibility data using scATAC-seqNCBI Gene Expression Omnibus, GSE65360.
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ATAC-seq dataNCBI Gene Expression Omnibus, GSE74912.
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Single-cell chromatin accessibility data using scATAC-seqNCBI Gene Expression Omnibus, GSE74310.
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Single-cell epigenomics maps the continuous regulatory landscape of human hematopoietic differentiationNCBI Gene Expression Omnibus, GSE96772.
Article and author information
Author details
Funding
National Human Genome Research Institute (P50-HG007735)
- Howard Y Chang
Howard Hughes Medical Institute
- Howard Y Chang
National Cancer Institute (R01HL142637)
- Ravindra Majeti
National Cancer Institute (R01CA188055)
- Ravindra Majeti
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: AML samples were obtained from patients at the Stanford Medical Center with informed consent, according to institutional review board (IRB)-approved protocols (Stanford IRB, 18329 and 6453).
Copyright
© 2019, Xu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Single-cell lineage tracing by endogenous mutations enriched in transposase accessible mitochondrial DNA
eLife 8:e45105.
https://doi.org/10.7554/eLife.45105
Further reading
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Why does a normal cell possibly harboring genetic mutations in oncogene or tumor suppressor genes becomes malignant and develops a tumor is a subject of intense debate. Various theories have been proposed but their experimental test has been hampered by the unpredictable and improbable malignant transformation of single cells. Here, using an optogenetic approach we permanently turn on an oncogene (KRASG12V) in a single cell of a zebrafish brain that, only in synergy with the transient co-activation of a reprogramming factor (VENTX/NANOG/OCT4), undergoes a deterministic malignant transition and robustly and reproducibly develops within 6 days into a full-blown tumor. The controlled way in which a single cell can thus be manipulated to give rise to cancer lends support to the ‘ground state theory of cancer initiation’ through ‘short-range dispersal’ of the first malignant cells preceding tumor growth.
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