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H3K27 Acetylation and Gene Expression Analysis Reveals Differences in Placental Chromatin Activity in Fetal Growth Restriction N

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H3K27 Acetylation and Gene Expression Analysis Reveals Differences in Placental Chromatin Activity in Fetal Growth Restriction N Paauw et al. Clinical Epigenetics (2018) 10:85 https://doi.org/10.1186/s13148-018-0508-x RESEARCH Open Access H3K27 acetylation and gene expression analysis reveals differences in placental chromatin activity in fetal growth restriction N. D. Paauw1,6*, A. T. Lely1, J. A. Joles2, A. Franx1, P. G. Nikkels3, M. Mokry4 and B. B. van Rijn1,5,6* 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. Keywords: ChIP-seq, Growth restriction, H3K27ac, Epigenetics, Histone acetylation, Placenta, Placental pathology, RNA-seq Background and distal enhancers, the most important and best under- The dynamics of histone 3 lysine 27 acetylation stood regulatory domains. To study involvement of this (H3K27ac) in DNA regulatory regions is one of the com- regulatory level/layer in placental pathology, we mapped ponents playing a fundamental role in the precise timing H3K27ac occupancy in healthy placentas and placentas and level of gene transcription [1, 2]. Consequently, aber- from pregnancies with fetal growth restriction (FGR). rant H3K27ac has been suggested to be involved in dis- FGR, a condition in which the fetus is unable to ease pathology by eliciting pathological gene expression achieve its full growth potential through inadequate sup- programs [3, 4]. H3K27ac marks both active promoters ply of nutrients and growth factors, occurs in approxi- mately 5% of pregnancies [5]. FGR imposes a major risk of perinatal morbidity and mortality [6] and programs * Correspondence: [email protected]; [email protected] the health of the fetus throughout life, by being associ- 1Department of Obstetrics, Wilhelmina Children’s Hospital Birth Center, University Medical Center Utrecht, Utrecht, the Netherlands ated with a future risk of type 2 diabetes and Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Paauw et al. Clinical Epigenetics (2018) 10:85 Page 2 of 11 cardiovascular and renal disease [7, 8]. At the histo- Genes annotated to within 20 kb of differentially pathological level, FGR placenta exhibit signs of dis- acetylated regions rupted placental development characterized by increased To identify the biological relevance of differentially acet- infarction area, increased syncytial knotting, inflamma- ylated peaks, we annotated genes to the hyper- and tion, and impaired trophoblast invasion into the spiral hypoacetylated sites using a window of ± 20 kb from arteries of the uterus due to inappropriate maternal-fetal transcription start site (TSS). We annotated 368 genes immune interaction [9–11]. corresponding to hyperacytelated sites and 313 genes as- Previous studies of placentas of FGR pregnancies have sociated with hypoacetylated sites (Additional file 1: reported differences in gene transcription across many re- Table S2). Several of these annotated genes are known to gions across the genome. Pathways associated with altered be involved in placental development. For instance, we placentalgeneexpressioninFGR include angiogenesis, im- found hyperacetylation of regions near HK2, FLT1, and mune modulation, energy production, and growth signaling LEP, previously reported to be upregulated in other pla- [12–15]. Most adaptive responses of the placenta, e.g., to cental disorders [25, 26], and hypoacetylation of regions support restricted fetal growth, are thought to result from near CH2 and CDLN1, which are involved in growth changes in epigenetic regulation [16–18]. Recently, DNA and endothelial cell-to-cell adhesions. The individual methylation has been mapped in the human placenta [19] peaks of selected regions of interest are presented in and a number of studies have suggested differences in Fig. 2a (near HK2) and Fig. 2b (near Flt-1, LEP, CDLN1, genome-wide methylation profiles in FGR placentas [20– and CH1). These figures show that sites identified to be 22]. We assume that disruptions in other epigenetic sys- differentially acetylated are highly similar across each of tems (e.g., histone modifications and other posttranslational the replicates. chromatin modifications) regulating placenta gene expres- sionarealsolikelytobeinvolved[23, 24]. Pathway analysis of differential acetylated regions in FGR In this study, we mapped differential H3K27ac profiles placentas in DNA regulatory regions in relation to disrupted devel- Next, we aimed to assign biological significance to genes opment of the placenta, by exploring the presence of annotated to differentially acetylated peaks by pathway H3K27ac using chromatin immunoprecipitation sequen- analysis using GREAT software. The software annotated cing (ChIP-seq) in FGR and control placentas. Next, we 515 genes to hyperacetylated regions in FGR. Although performed RNA-seq to examine whether differences in no enrichment for GO biological process or for path- H3K27ac also reflects gene expression levels. With this ways was identified using this approach, the annotated approach, we identified previously unstudied alterations in genes were enriched for genes that are transcriptionally promoter and enhancer activity related to placenta regulated by HIF-1-alfa/hypoxia within the MSigDB per- pathology. turbation ontology (full output supplied in Add- itional file 1: Table S3). Other functional pathways Results related to hyperacetylated regions include pathways in- Detection of regions with differential H3K27ac occupancy volved in cancer and immune response. Nearby the dif- First, we performed genome-wide analysis of H3K27ac by ferential hypoacetylated regions, GREAT identified 868 ChIP-seq on placental tissue from control (n = 4) and FGR genes. GO biological processes and pathways related to pregnancies (n = 5) and identified 30,288 H3K27ac peaks these genes consisted of angiogenesis, response to exter- that were present in at least two independent samples. Of nal signals, and immune activation (Fig. 3a, b, full output these, 970 regions showed differential H3K27ac levels in supplied in Additional file 1: Table S3). Interestingly, FGR compared to controls with 366 being hyperacetylated many of these pathways are known to be disrupted in and 604 regions being hypoacetylated in FGR (Fig. 1a,full FGR, especially angiogenesis, HIF-1-alpha signaling, and list supplied in Additional file 1: Table S1). Based on the the immune environment/response [27–29]. differentially acetylated regions, the FGR and healthy pla- centas could be clearly segregated using both supervised Cross-validation of functional effects by combining and unsupervised analysis (Fig. 1b–c,Additionalfile2) H3K27ac and mRNA profiles These findings indicate clear distinction between the two To cross-validate functional meaning of the differentially groups and suggest a specific and highly reproducible acetylated peaks and to examine whether hyper- or H3K27ac pattern in FGR placentas. Differentially acety- hypoacetylated state of H3K27 was also accompanied by lated regions were distributed throughout the whole gen- differential gene expression, we performed RNA-seq. We ome as shown by Manhattan
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