The University of Southampton
University of Southampton Institutional Repository

H3K27 acetylation and gene expression analysis reveals differences in placental chromatin activity in fetal growth restriction

H3K27 acetylation and gene expression analysis reveals differences in placental chromatin activity in fetal growth restriction
H3K27 acetylation and gene expression analysis reveals differences in placental chromatin activity in fetal growth restriction

Background: Posttranslational modification of histone tails such as histone 3 lysine 27 acetylation (H3K27ac) is tightly coupled to epigenetic regulation of gene expression. To explore whether this is involved in placenta pathology, we probed genome-wide H3K27ac occupancy by chromatin immunoprecipitation sequencing (ChIP-seq) in healthy placentas and placentas from pathological pregnancies with fetal growth restriction (FGR). Furthermore, we related specific acetylation profiles of FGR placentas to gene expression changes. Results: Analysis of H3K27ac occupancy in FGR compared to healthy placentas showed 970 differentially acetylated regions distributed throughout the genome. Principal component analysis and hierarchical clustering revealed complete segregation of the FGR and control group. Next, we identified 569 upregulated genes and 521 downregulated genes in FGR placentas by RNA sequencing. Differential gene transcription largely corresponded to expected direction based on H3K27ac status. Pathway analysis on upregulated transcripts originating from hyperacetylated sites revealed genes related to the HIF-1-alpha transcription factor network and several other genes with known involvement in placental pathology (LEP, FLT1, HK2, ENG, FOS). Downregulated transcripts in the vicinity of hypoacetylated sites were related to the immune system and growth hormone receptor signaling. Additionally, we found enrichment of 141 transcription factor binding motifs within differentially acetylated regions. Of the corresponding transcription factors, four were upregulated, SP1, ARNT2, HEY2, and VDR, and two downregulated, FOSL and NR4A1. Conclusion: We demonstrate a key role for genome-wide alterations in H3K27ac in FGR placentas corresponding with changes in transcription profiles of regions relevant to placental function. Future studies on the role of H3K27ac in FGR and placental-fetal development may help to identify novel targets for therapy of this currently incurable disease.

ChIP-seq, Epigenetics, Growth restriction, H3K27ac, Histone acetylation, Placenta, Placental pathology, RNA-seq
1868-7075
Paauw, N.D.
c90d2be6-b2a8-454a-827d-c58fd518e7fe
Lely, A.T.
0c34bf2f-7178-4c70-be7a-c64355d7f9e2
Joles, J.A.
911a0118-2e68-471f-9f54-7662d77f725d
Franx, A.
4458abd6-e106-46b2-a448-f2e6a250fd00
Nikkels, P.G.
78411d4e-ea80-48f0-aba7-ffc24882694a
Mokry, M.
d3d7eb00-1c39-4521-92b7-5c03b31eb7d4
van Rijn, B.B.
c958dfb5-2010-46de-a350-4903295ac340
Paauw, N.D.
c90d2be6-b2a8-454a-827d-c58fd518e7fe
Lely, A.T.
0c34bf2f-7178-4c70-be7a-c64355d7f9e2
Joles, J.A.
911a0118-2e68-471f-9f54-7662d77f725d
Franx, A.
4458abd6-e106-46b2-a448-f2e6a250fd00
Nikkels, P.G.
78411d4e-ea80-48f0-aba7-ffc24882694a
Mokry, M.
d3d7eb00-1c39-4521-92b7-5c03b31eb7d4
van Rijn, B.B.
c958dfb5-2010-46de-a350-4903295ac340

Paauw, N.D., Lely, A.T., Joles, J.A., Franx, A., Nikkels, P.G., Mokry, M. and van Rijn, B.B. (2018) H3K27 acetylation and gene expression analysis reveals differences in placental chromatin activity in fetal growth restriction. Clinical Epigenetics, 10 (1), [85]. (doi:10.1186/s13148-018-0508-x).

Record type: Article

Abstract

Background: Posttranslational modification of histone tails such as histone 3 lysine 27 acetylation (H3K27ac) is tightly coupled to epigenetic regulation of gene expression. To explore whether this is involved in placenta pathology, we probed genome-wide H3K27ac occupancy by chromatin immunoprecipitation sequencing (ChIP-seq) in healthy placentas and placentas from pathological pregnancies with fetal growth restriction (FGR). Furthermore, we related specific acetylation profiles of FGR placentas to gene expression changes. Results: Analysis of H3K27ac occupancy in FGR compared to healthy placentas showed 970 differentially acetylated regions distributed throughout the genome. Principal component analysis and hierarchical clustering revealed complete segregation of the FGR and control group. Next, we identified 569 upregulated genes and 521 downregulated genes in FGR placentas by RNA sequencing. Differential gene transcription largely corresponded to expected direction based on H3K27ac status. Pathway analysis on upregulated transcripts originating from hyperacetylated sites revealed genes related to the HIF-1-alpha transcription factor network and several other genes with known involvement in placental pathology (LEP, FLT1, HK2, ENG, FOS). Downregulated transcripts in the vicinity of hypoacetylated sites were related to the immune system and growth hormone receptor signaling. Additionally, we found enrichment of 141 transcription factor binding motifs within differentially acetylated regions. Of the corresponding transcription factors, four were upregulated, SP1, ARNT2, HEY2, and VDR, and two downregulated, FOSL and NR4A1. Conclusion: We demonstrate a key role for genome-wide alterations in H3K27ac in FGR placentas corresponding with changes in transcription profiles of regions relevant to placental function. Future studies on the role of H3K27ac in FGR and placental-fetal development may help to identify novel targets for therapy of this currently incurable disease.

Text
document - Version of Record
Available under License Creative Commons Attribution.
Download (3MB)

More information

Accepted/In Press date: 29 May 2018
e-pub ahead of print date: 26 June 2018
Keywords: ChIP-seq, Epigenetics, Growth restriction, H3K27ac, Histone acetylation, Placenta, Placental pathology, RNA-seq

Identifiers

Local EPrints ID: 422112
URI: http://eprints.soton.ac.uk/id/eprint/422112
ISSN: 1868-7075
PURE UUID: 29995b5f-728b-4b87-8c84-077c2846eb59

Catalogue record

Date deposited: 17 Jul 2018 16:30
Last modified: 06 Oct 2020 16:56

Export record

Altmetrics

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×