Regulation of human trophoblast gene expression by endogenous retroviruses
Regulation of human trophoblast gene expression by endogenous retroviruses
The placenta is a fast-evolving organ with large morphological and histological differences across eutherians, but the genetic changes driving placental evolution have not been fully elucidated. Transposable elements, through their capacity to quickly generate genetic variation and affect host gene regulation, may have helped to define species-specific trophoblast gene expression programs. Here we assess the contribution of transposable elements to human trophoblast gene expression as enhancers or promoters. Using epigenomic data from primary human trophoblast and trophoblast stem-cell lines, we identified multiple endogenous retrovirus families with regulatory potential that lie close to genes with preferential expression in trophoblast. These largely primate-specific elements are associated with inter-species gene expression differences and are bound by transcription factors with key roles in placental development. Using genetic editing, we demonstrate that several elements act as transcriptional enhancers of important placental genes, such as CSF1R and PSG5. We also identify an LTR10A element that regulates ENG expression, affecting secretion of soluble endoglin, with potential implications for preeclampsia. Our data show that transposons have made important contributions to human trophoblast gene regulation, and suggest that their activity may affect pregnancy outcomes.
527–538
Frost, Jennifer M
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Amante, Samuele M
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Okae, Hiroaki
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Jones, Eleri M
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Ashley, Brogan
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Lewis, Rohan M
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Cleal, Jane K
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Caley, Matthew P
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Arima, Takahiro
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Maffucci, Tania
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Branco, Miguel R
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3 April 2023
Frost, Jennifer M
3049ba0e-882b-4249-b67c-f963d0c17e67
Amante, Samuele M
c911ec73-2cb1-452f-98e8-b89c6732d381
Okae, Hiroaki
7589a944-cb2d-4e17-9531-55b91b26a81f
Jones, Eleri M
9ac7a750-f4cd-4d54-8bcb-2675bc3512be
Ashley, Brogan
869e37c8-67c4-4702-8f4c-84a5bc431eaa
Lewis, Rohan M
caaeb97d-ea69-4f7b-8adb-5fa25e2d3502
Cleal, Jane K
18cfd2c1-bd86-4a13-b38f-c321af56da66
Caley, Matthew P
cec65c2a-be10-4667-90e6-cf093743d799
Arima, Takahiro
7767fbea-f4d1-45e7-9a0a-daa2d54664ba
Maffucci, Tania
56942160-25c2-4d50-9002-fecf3bd1ee69
Branco, Miguel R
e63a3f97-f356-4fba-b84a-23dadf7410b9
Frost, Jennifer M, Amante, Samuele M, Okae, Hiroaki, Ashley, Brogan, Lewis, Rohan M and Cleal, Jane K
,
et al.
(2023)
Regulation of human trophoblast gene expression by endogenous retroviruses.
Nature structural & molecular biology, 30 (4), .
(doi:10.1038/s41594-023-00960-6).
Abstract
The placenta is a fast-evolving organ with large morphological and histological differences across eutherians, but the genetic changes driving placental evolution have not been fully elucidated. Transposable elements, through their capacity to quickly generate genetic variation and affect host gene regulation, may have helped to define species-specific trophoblast gene expression programs. Here we assess the contribution of transposable elements to human trophoblast gene expression as enhancers or promoters. Using epigenomic data from primary human trophoblast and trophoblast stem-cell lines, we identified multiple endogenous retrovirus families with regulatory potential that lie close to genes with preferential expression in trophoblast. These largely primate-specific elements are associated with inter-species gene expression differences and are bound by transcription factors with key roles in placental development. Using genetic editing, we demonstrate that several elements act as transcriptional enhancers of important placental genes, such as CSF1R and PSG5. We also identify an LTR10A element that regulates ENG expression, affecting secretion of soluble endoglin, with potential implications for preeclampsia. Our data show that transposons have made important contributions to human trophoblast gene regulation, and suggest that their activity may affect pregnancy outcomes.
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More information
Accepted/In Press date: 2 March 2023
e-pub ahead of print date: 3 April 2023
Published date: 3 April 2023
Additional Information:
Funding Information:
We thank J. Kropp Schmidt and T. Golos for sharing their macaque TSC RNA-seq data, S. Henikoff (Fred Hutchinson Cancer Research Center), P. Madapura (QMUL), H. Wan (QMUL) and P. Hurd (QMUL) for reagents, and S. Papa (Univ. Leeds) for insights into the complexities of JNK activity. We also thank G. Warnes for his gracious assistance with FACS. This work was supported by the BBSRC (research grant no. BB/T000031/1, awarded to M.B. and J.F.), Barts Charity (MRC0297, awarded to M.B. and J.F.) and The Leakey Foundation (awarded to J.F.). This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement InvADeRS no. 841172 (to J.F.).
Publisher Copyright:
© 2023, The Author(s).
Identifiers
Local EPrints ID: 476304
URI: http://eprints.soton.ac.uk/id/eprint/476304
ISSN: 1545-9985
PURE UUID: 4a89c311-dad1-4615-9a2d-c001a7a5c629
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Date deposited: 19 Apr 2023 16:33
Last modified: 15 Aug 2024 01:37
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Contributors
Author:
Jennifer M Frost
Author:
Samuele M Amante
Author:
Hiroaki Okae
Author:
Eleri M Jones
Author:
Brogan Ashley
Author:
Matthew P Caley
Author:
Takahiro Arima
Author:
Tania Maffucci
Author:
Miguel R Branco
Corporate Author: et al.
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