A new human embryonic cell type associated with activity of young transposable elements allows definition of the inner cell mass

Manvendra Singh, Aleksandra M. Kondrashkina, Thomas J. Widmann, Jose L. Cortes, Vikas Bansa, Jichang Wang, Christine Romer, Marta Garcia-Canadas, Jose L. Garcia-Perez, Laurence D. Hurst, Zsuzsanna Izsvak

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Abstract

There remains much that we do not understand about the earPlileesatsesvtaergiefysthoaftahlulemntarniedsaerveecloorpr-ect: ment. On a gross level, there is evidence for apoptosis, but the nature of the affected cell types is unknown. Perhaps most importantly, the inner cell mass (ICM), from which the foetus is derived and hence of interest in reproductive health and regenerative medicine, has proven hard to define. Here, we provide a multi-method analysis of the early human embryo to resolve these issues. Single-cell analysis (on multiple independent datasets), supported by embryo visualisation, uncovers a common previously uncharacterised class of cells lacking commitment markers that segregates after embryonic gene activation (EGA) and shortly after undergo apoptosis. The discovery of this cell type allows us to clearly define their viable ontogenetic sisters, these being the cells of the ICM. While ICM is characterised by the activity of an Old non-transposing endogenous retrovirus (HERVH) that acts to suppress Young transposable elements, the new cell type, by contrast, expresses transpositionally competent Young elements and DNA-damage response genes. As the Young elements are RetroElements and the cells are excluded from the developmental process, we dub these REject cells. With these and ICM being characterised by differential mobile element activities, the human embryo may be a "selection arena" in which one group of cells selectively die, while other less damaged cells persist.

Original languageEnglish
Article numbere3002162
JournalPLoS Biology
Volume21
Issue number6
DOIs
Publication statusPublished - 20 Jun 2023

Bibliographical note

Funding:
Z.I. was funded by European Research Council, ERC Advanced [ERC-2011-ADG 294742]. L.D.H. is funded by European Research Council, ERC Advanced [ERC-2014-ADG 669207]. J.L.G.P´s lab is supported by CICE-FEDER-P12-CTS-2256, Plan Nacional de I+D+I 2008-2011 and 2013-2016 (FIS-FEDER-PI14/02152), PCIN-2014-115-ERA-NET NEURON II, the European Research Council (ERC-Consolidator ERC-STG-2012-309433), by an International Early Career Scientist grant from the Howard Hughes Medical Institute (IECS-55007420), by The Wellcome Trust-University of Edinburgh Institutional Strategic Support Fund (ISFF2) and by a private donation by Ms Francisca Serrano (Trading y Bolsa para Torpes, Granada, Spain). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data Availability:
All data sources are noted in text or available as supplementary tables. The sources are: human pre-implantation lineages: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE36552 , https://www.ebi.ac.uk/biostudies/arrayexpress/studies/E-MTAB-3929 https://ega-archive.org/studies/EGAS00001003667 Cynomolgus pre-implantation embryogenesis: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE74767 Mouse blastocyst samples: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE45719 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE57249 ATAC-seq and RNAseq datasets from human 8-cell, bulk ICM, naïve and hESCs: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE101571 ChIP-STARR-seq: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE99631, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE54471 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE35583 All code is available from: doi.org/10.5281/zenodo.7925199.

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry,Genetics and Molecular Biology
  • General Immunology and Microbiology
  • General Agricultural and Biological Sciences

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