Mosaic cis-regulatory evolution drives transcriptional partitioning of HERVH endogenous retrovirus in the human embryo
- Cornell University, United States [US]
- Cornell University, United States
- University of Colorado Boulder, United States
Abstract
The human endogenous retrovirus type-H (HERVH) family is expressed in the preimplantation embryo. A subset of these elements are specifically transcribed in pluripotent stem cells where they appear to exert regulatory activities promoting self-renewal and pluripotency. How HERVH elements achieve such transcriptional specificity remains poorly understood. To uncover the sequence features underlying HERVH transcriptional activity, we performed a phyloregulatory analysis of the long terminal repeats (LTR7) of the HERVH family, which harbor its promoter, using a wealth of regulatory genomics data. We found that the family includes at least 8 previously unrecognized subfamilies that have been active at different timepoints in primate evolution and display distinct expression patterns during human embryonic development. Notably, nearly all HERVH elements transcribed in ESCs belong to one of the youngest subfamilies we dubbed LTR7up. LTR7 sequence evolution was driven by a mixture of mutational processes, including point mutations, duplications, and multiple recombination events between subfamilies, that led to transcription factor binding motif modules characteristic of each subfamily. Using a reporter assay, we show that one such motif, a predicted SOX2/3 binding site unique to LTR7up, is essential for robust promoter activity in induced pluripotent stem cells. Together these findings illuminate the mechanisms by which HERVH diversified its expression pattern during evolution to colonize distinct cellular niches within the human embryo.
Data availability
Scripts, data tables, and notes for figures 1-4,6a and supplemental figures 1-1,2-1,3-1,4-1,5-1,6-2 by TAC and JDC - https://github.com/LumpLord/Mosaic-cis-regulatory-evolution-drives-transcriptional-partitioning-of-HERVH-endogenous-retrovirus..Scripts and data tables by MS for figures 5,6c and supplemental figures 6-1,6-3,5-2 - https://github.com/Manu-1512/LTR7-up
-
Transcription factor binding dynamics during human ES cell differentiationNCBI Gene Expression Omnibus, GSE61475.
-
3D Chromosome Regulatory Landscape of Human Pluripotent CellsNCBI Gene Expression Omnibus, GSE69647.
-
ChIP-exo of human KRAB-ZNFs transduced in HEK 293T cells and KAP1 in hES H1 cellsNCBI Gene Expression Omnibus, GSE78099.
-
Repeat elements study in pluripotent stem cellsNCBI Gene Expression Omnibus, GSE54726.
-
Principles of Signalling Pathway Modulation for Enhancing Human Naïve Pluripotency Induction [ChIP-seq]NCBI Gene Expression Omnibus, GSE125553.
-
Tracing pluripotency of human early embryos and embryonic stem cells by single cell RNA-seqNCBI Gene Expression Omnibus, GSE36552.
-
Single-Cell RNA-seq Defines the Three Cell Lineages of the Human BlastocystNCBI Gene Expression Omnibus, GSE66507.
Article and author information
Author details
Funding
National Institutes of Health (GM112972)
- Cédric Feschotte
National Institutes of Health (HG009391)
- Cédric Feschotte
National Institutes of Health (GM122550)
- Cédric Feschotte
Cornell Center for Vertebrate Genomics
- Thomas Carter
Howard Hughes Medical Institute
- John L Rinn
National Institutes of Health (GM099117)
- John L Rinn
Cornell Presidential Fellow Program
- Manvendra Singh
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Carter 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
-
- 3,976
- views
-
- 462
- downloads
-
- 39
- 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)
Mosaic cis-regulatory evolution drives transcriptional partitioning of HERVH endogenous retrovirus in the human embryo
eLife 11:e76257.
https://doi.org/10.7554/eLife.76257
Further reading
-
- Evolutionary Biology
- Genetics and Genomics
Cattle (Bos taurus) play an important role in the life of humans in the Iberian Peninsula not just as a food source but also in cultural events. When domestic cattle were first introduced to Iberia, wild aurochs (Bos primigenius) were still present, leaving ample opportunity for mating (whether intended by farmers or not). Using a temporal bioarchaeological dataset covering eight millennia, we trace gene flow between the two groups. Our results show frequent hybridisation during the Neolithic and Chalcolithic, likely reflecting a mix of hunting and herding or relatively unmanaged herds, with mostly male aurochs and female domestic cattle involved. This is supported by isotopic evidence consistent with ecological niche sharing, with only a few domestic cattle possibly being managed. The proportion of aurochs ancestry in domestic cattle remains relatively constant from about 4000 years ago, probably due to herd management and selection against first generation hybrids, coinciding with other cultural transitions. The constant level of wild ancestry (~20%) continues into modern Western European breeds including Iberian cattle selected for aggressiveness and fighting ability. This study illuminates the genomic impact of human actions and wild introgression in the establishment of cattle as one of the most important domestic species today.
-
- Genetics and Genomics
Becker muscular dystrophy (BMD), an X-linked muscular dystrophy, is mostly caused by an in-frame deletion of Duchenne muscular dystrophy (DMD). BMD severity varies from asymptomatic to severe, associated with the genotype of DMD. However, the underlying mechanisms remain unclear. We established BMD mice carrying three representative exon deletions: ex45–48 del., ex45–47 del., and ex45–49 del. (d45–48, d45–47, and d45–49), with high frequencies and different severities in the human BMD hotspot. All three BMD mice showed muscle weakness, muscle degeneration, and fibrosis, but these changes appeared at different times for each exon deletion, consistent with the severities obtained by the natural history study of BMD. BMD mice showed site-specific muscle changes, unlike mdx mice, which showed diffuse muscle changes, and we demonstrated selective type IIa fiber reduction in BMD mice. Furthermore, BMD mice showed sarcolemmal neuronal nitric oxide synthase (nNOS) reduction and morphological capillary changes around type IIa fibers. These results suggest that capillary changes caused by nNOS reduction may be associated with the mechanism of skeletal muscle degeneration and type IIa fiber reduction in BMD mice. BMD mice may be useful in elucidating the pathomechanisms and developing vascular targeted therapies for human BMD.
