Enforcement of developmental lineage specificity by transcription factor Oct1

  1. Zuolian Shen
  2. Jinsuk Kang
  3. Arvind Shakya
  4. Marcin Tabaka
  5. Elke A Jarboe
  6. Aviv Regev
  7. Dean Tantin  Is a corresponding author
  1. Celgene Corporation, United States
  2. The Broad Institute of MIT and Harvard, United States
  3. University of Utah School of Medicine, United States

Abstract

Embryonic stem cells co-express Oct4 and Oct1, a related protein with similar DNA binding specificity. To study the role of Oct1 in ESC pluripotency and transcriptional control, we constructed germline and inducible-conditional Oct1 deficient ESC lines. ESCs lacking Oct1 show normal appearance, self-renewal and growth, but manifest defects upon differentiation. They fail to form beating cardiomyocytes, generate neurons poorly, form small, poorly differentiated teratomas, and cannot generate chimeric mice. Upon RA-mediated differentiation, Oct1 deficient cells induce lineage-appropriate developmentally poised genes poorly while lineage-inappropriate genes, including extra-embryonic genes, are inappropriately expressed. In ESCs Oct1 co-occupies a specific set of targets with Oct4, but does not occupy differentially expressed developmental targets. Instead, Oct1 occupies these targets as cells differentiate and Oct4 declines. These results identify a dynamic interplay between Oct1 and Oct4, in particular during the critical window immediately after loss of pluripotency when cells make the earliest developmental fate decisions.

Data availability

The following data sets were generated

Article and author information

Author details

  1. Zuolian Shen

    Celgene Corporation, San Diego, United States
    Competing interests
    No competing interests declared.
  2. Jinsuk Kang

    Celgene Corporation, San Diego, United States
    Competing interests
    No competing interests declared.
  3. Arvind Shakya

    Celgene Corporation, San Diego, United States
    Competing interests
    No competing interests declared.
  4. Marcin Tabaka

    The Broad Institute of MIT and Harvard, Cambridge, United States
    Competing interests
    No competing interests declared.
  5. Elke A Jarboe

    Department of Pathology, University of Utah School of Medicine, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  6. Aviv Regev

    The Broad Institute of MIT and Harvard, Cambridge, United States
    Competing interests
    Aviv Regev, Senior editor, eLife.
  7. Dean Tantin

    Department of Pathology, University of Utah School of Medicine, Salt Lake City, United States
    For correspondence
    dean.tantin@path.utah.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1354-8385

Funding

National Institute of Allergy and Infectious Diseases (R01AI100873)

  • Dean Tantin

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#14-06015) of the University of Utah. Every effort was made to minimize suffering.

Copyright

© 2017, Shen 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

  • 1,540
    views
  • 225
    downloads
  • 16
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  1. Zuolian Shen
  2. Jinsuk Kang
  3. Arvind Shakya
  4. Marcin Tabaka
  5. Elke A Jarboe
  6. Aviv Regev
  7. Dean Tantin
(2017)
Enforcement of developmental lineage specificity by transcription factor Oct1
eLife 6:e20937.
https://doi.org/10.7554/eLife.20937

Share this article

https://doi.org/10.7554/eLife.20937

Further reading

    1. Developmental Biology
    Nathaniel C Nelson, Matthias C Kugler
    Insight

    Cells called alveolar myofibroblasts, which have a central role in the development of the lung after birth, receive an orchestrated input from a range of different signaling pathways.

    1. Developmental Biology
    Imran S Khan, Christopher Molina ... Dean Sheppard
    Research Article

    Premature infants with bronchopulmonary dysplasia (BPD) have impaired alveolar gas exchange due to alveolar simplification and dysmorphic pulmonary vasculature. Advances in clinical care have improved survival for infants with BPD, but the overall incidence of BPD remains unchanged because we lack specific therapies to prevent this disease. Recent work has suggested a role for increased transforming growth factor-beta (TGFβ) signaling and myofibroblast populations in BPD pathogenesis, but the functional significance of each remains unclear. Here, we utilize multiple murine models of alveolar simplification and comparative single-cell RNA sequencing to identify shared mechanisms that could contribute to BPD pathogenesis. Single-cell RNA sequencing reveals a profound loss of myofibroblasts in two models of BPD and identifies gene expression signatures of increased TGFβ signaling, cell cycle arrest, and impaired proliferation in myofibroblasts. Using pharmacologic and genetic approaches, we find no evidence that increased TGFβ signaling in the lung mesenchyme contributes to alveolar simplification. In contrast, this is likely a failed compensatory response, since none of our approaches to inhibit TGFβ signaling protect mice from alveolar simplification due to hyperoxia while several make simplification worse. In contrast, we find that impaired myofibroblast proliferation is a central feature in several murine models of BPD, and we show that inhibiting myofibroblast proliferation is sufficient to cause pathologic alveolar simplification. Our results underscore the importance of impaired myofibroblast proliferation as a central feature of alveolar simplification and suggest that efforts to reverse this process could have therapeutic value in BPD.