H3K27 acetylation and gene expression analysis reveals differences in placental chromatin activity in fetal growth restriction
Autor: | Jaap A. Joles, Peter G. J. Nikkels, Michal Mokry, A. T. Lely, Arie Franx, B. B. van Rijn, Nina D. Paauw |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Chromatin Immunoprecipitation lcsh:QH426-470 Placenta lcsh:Medicine Epigenesis Genetic Fetal Development Histones 03 medical and health sciences Transcription (biology) Pregnancy Gene expression Genetics Humans Genetics(clinical) Epigenetics HEY2 Gene Transcription factor Molecular Biology Genetics (clinical) Fetal Growth Retardation biology Sequence Analysis RNA Research lcsh:R Growth restriction Acetylation Receptors Somatotropin H3K27ac Hypoxia-Inducible Factor 1 alpha Subunit Chromatin Cell biology Placental pathology ChIP-seq lcsh:Genetics 030104 developmental biology Histone Histone acetylation biology.protein Female RNA-seq Protein Processing Post-Translational Developmental Biology Transcription Factors |
Zdroj: | Clinical Epigenetics, 10(1). Springer Verlag Clinical Epigenetics, Vol 10, Iss 1, Pp 1-11 (2018) Clinical Epigenetics |
ISSN: | 1868-7083 1868-7075 |
Popis: | 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. Electronic supplementary material The online version of this article (10.1186/s13148-018-0508-x) contains supplementary material, which is available to authorized users. |
Databáze: | OpenAIRE |
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