1. Evolutionary Biology
  2. Genetics and Genomics
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Evolutionary transcriptomics implicates HAND2 in the origins of implantation and regulation of gestation length

  1. Mirna Marinić
  2. Katelyn Mika
  3. Sravanthi Chigurupati
  4. Vincent J Lynch  Is a corresponding author
  1. University of Chicago, United States
  2. AbbVie, United States
  3. University at Buffalo, United States
Research Article
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Cite this article as: eLife 2021;10:e61257 doi: 10.7554/eLife.61257

Abstract

The developmental origins and evolutionary histories of cell types, tissues and organ systems contribute to the ways in which their dysfunction leads to disease. In mammals for example, the nature and extent of maternal-fetal interactions, how those interactions develop, and their evolutionary history likely influence diseases of pregnancy such as infertility and preterm birth. Here we show genes that evolved to be expressed at the maternal-fetal interface in Eutherian ('Placental') mammals play essential roles in the evolution of pregnancy and are associated with immune system disorders and preterm birth. Among these genes is the transcription factor HAND2, which suppresses estrogen signaling, an innovation of Eutherians, thereby allowing blastocyst implantation. We found that HAND2 is dynamically expressed in the decidua throughout the menstrual cycle and pregnancy, gradually decreasing to reach a low at term. HAND2 regulates a small but distinct set of target genes in endometrial stromal fibroblasts including the cytokine IL15, which was also dynamically expressed throughout the menstrual cycle and gestation, and promoted the migration of natural killer cells and extravillous cytotrophoblasts. Remarkably, we found that the HAND2 promoter loops to a distal enhancer containing SNPs implicated in the regulation of gestation length and birth weight. Collectively, these data connect HAND2 expression at the maternal-fetal interface with the evolution of implantation and gestation length regulation, and preterm birth.

Article and author information

Author details

  1. Mirna Marinić

    Organismal Biology and Anatomy, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7037-8389
  2. Katelyn Mika

    Department of Human Genetics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Sravanthi Chigurupati

    AbbVie, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Vincent J Lynch

    Department of Biological Sciences, University at Buffalo, Buffalo, United States
    For correspondence
    vjlynch@buffalo.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5311-3824

Funding

Burroughs Wellcome Fund (Preterm Birth Initiative,1013760)

  • Vincent J Lynch

March of Dimes Foundation (Prematurity Research Center)

  • Vincent J Lynch

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

Reviewing Editor

  1. Antonis Rokas, Vanderbilt University, United States

Publication history

  1. Received: July 20, 2020
  2. Accepted: January 29, 2021
  3. Accepted Manuscript published: February 1, 2021 (version 1)

Copyright

© 2021, Marinić 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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