1. Cancer Biology
  2. Genetics and Genomics
Download icon

Single-cell lineage tracing by endogenous mutations enriched in transposase accessible mitochondrial DNA

  1. Jin Xu
  2. Kevin Nuno
  3. Ulrike M Litzenburger
  4. Yanyan Qi
  5. M Ryan Corces  Is a corresponding author
  6. Ravindra Majeti  Is a corresponding author
  7. Howard Y Chang  Is a corresponding author
  1. Stanford University, United States
Short Report
  • Cited 28
  • Views 7,837
  • Annotations
Cite this article as: eLife 2019;8:e45105 doi: 10.7554/eLife.45105

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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Jin Xu

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0944-9835

  2. Kevin Nuno

    Department of Medicine, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  3. Ulrike M Litzenburger

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  4. Yanyan Qi

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  5. M Ryan Corces

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    For correspondence
    rcorces@stanford.edu
    Competing interests
    No competing interests declared.

  6. Ravindra Majeti

    Department of Medicine, Stanford University, Stanford, United States
    For correspondence
    rmajeti@stanford.edu
    Competing interests
    Ravindra Majeti, Reviewing editor, eLife.

  7. Howard Y Chang

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    For correspondence
    howchang@stanford.edu
    Competing interests
    Howard Y Chang, is a co-founder of Accent Therapeutics and an advisor for 10x Genomics and Spring Discovery. Stanford University has filed a patent on ATAC-seq(US20160060691A1), on which HYC is named as an inventor..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9459-4393

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).

Reviewing Editor

  1. Ross L Levine, Memorial Sloan Kettering Cancer Center, United States

Publication history

  1. Received: January 12, 2019
  2. Accepted: April 7, 2019
  3. Accepted Manuscript published: April 8, 2019 (version 1)
  4. Accepted Manuscript updated: April 9, 2019 (version 2)
  5. Version of Record published: April 17, 2019 (version 3)

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.

Metrics

  • 7,837
    Page views
  • 1,071
    Downloads
  • 28
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Categories and tags

Research organism

Further reading

    1. Cancer Biology
    2. Cell Biology

    Defective apoptotic cell contractility provokes sterile inflammation leading to liver damage and tumour suppression

    Linda Julian et al.
    Research Article

    Apoptosis is characterized by profound morphological changes, but their physiological purpose is unknown. To characterize the role of apoptotic cell contraction, ROCK1 was rendered caspase non-cleavable (ROCK1nc) by mutating Aspartate 1113, which revealed that ROCK1 cleavage was necessary for forceful contraction and membrane blebbing. When homozygous ROCK1nc mice were treated with the liver-selective apoptotic stimulus of diethylnitrosamine, ROCK1nc mice had more profound liver damage with greater neutrophil infiltration than wild-type mice. Inhibition of the damage associated molecular pattern protein HMGB1 or signalling by its cognate receptor TLR4 lowered neutrophil infiltration and reduced liver damage. ROCK1nc mice also developed fewer diethylnitrosamine-induced hepatocellular carcinoma (HCC) tumours, while HMGB1 inhibition increased HCC tumour numbers. Thus, ROCK1 activation and consequent cell contraction are required to limit sterile inflammation and damage amplification following tissue-scale cell death. Additionally, these findings reveal a previously unappreciated role for acute sterile inflammation as an efficient tumour suppressive mechanism.

    1. Cancer Biology
    2. Developmental Biology

    An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma

    Rediet Zewdu et al.
    Research Article

    Cancer cells undergo lineage switching during natural progression and in response to therapy. NKX2-1 loss in human and murine lung adenocarcinoma leads to invasive mucinous adenocarcinoma (IMA), a lung cancer subtype that exhibits gastric differentiation and harbors a distinct spectrum of driver oncogenes. In murine BRAFV600E driven lung adenocarcinoma, NKX2-1 is required for early tumorigenesis, but dispensable for established tumor growth. NKX2-1-deficient, BRAFV600E driven tumors resemble human IMA and exhibit a distinct response to BRAF/MEK inhibitors. Whereas BRAF/MEK inhibitors drive NKX2-1-positive tumor cells into quiescence, NKX2-1-negative cells fail to exit the cell cycle after the same therapy. BRAF/MEK inhibitors induce cell identity switching in NKX2-1-negative lung tumors within the gastric lineage, which is driven in part by WNT signaling and FoxA1/2. These data elucidate a complex, reciprocal relationship between lineage specifiers and oncogenic signaling pathways in the regulation of lung adenocarcinoma identity that is likely to impact lineage-specific therapeutic strategies.

    1. Cancer Biology
    2. Cell Biology

    The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals

    Margaret E Torrence et al.
    Research Article Updated

    The mechanistic target of rapamycin complex 1 (mTORC1) stimulates a coordinated anabolic program in response to growth-promoting signals. Paradoxically, recent studies indicate that mTORC1 can activate the transcription factor ATF4 through mechanisms distinct from its canonical induction by the integrated stress response (ISR). However, its broader roles as a downstream target of mTORC1 are unknown. Therefore, we directly compared ATF4-dependent transcriptional changes induced upon insulin-stimulated mTORC1 signaling to those activated by the ISR. In multiple mouse embryo fibroblast and human cancer cell lines, the mTORC1-ATF4 pathway stimulated expression of only a subset of the ATF4 target genes induced by the ISR, including genes involved in amino acid uptake, synthesis, and tRNA charging. We demonstrate that ATF4 is a metabolic effector of mTORC1 involved in both its established role in promoting protein synthesis and in a previously unappreciated function for mTORC1 in stimulating cellular cystine uptake and glutathione synthesis.