1Department of Obstetrics, Wilhelmina Children's Hospital Birth Center, University Medical Center Utrecht, Utrecht, the Netherlands.
6Division Woman and Baby, University Medical Center Utrecht, Postbus 85090, 3508 AB Utrecht, the Netherlands.
Clin Epigenetics. 2018 Jun 26;10:85. doi: 10.1186/s13148-018-0508-x. eCollection 2018.
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.
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.
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.
组蛋白尾部的翻译后修饰，如组蛋白 3 赖氨酸 27 乙酰化（H3K27ac），与基因表达的表观遗传调控紧密相关。为了探讨这是否与胎盘病理学有关，我们通过染色质免疫沉淀测序（ChIP-seq）在健康胎盘和胎儿生长受限（FGR）的病理性妊娠胎盘上探测了全基因组范围内的 H3K27ac 占有率。此外，我们将 FGR 胎盘的特定乙酰化图谱与基因表达变化联系起来。
与健康胎盘相比，在 FGR 中分析 H3K27ac 占有率显示，分布在整个基因组中的 970 个差异乙酰化区域。主成分分析和层次聚类显示，FGR 和对照组完全分离。接下来，我们通过 RNA 测序在 FGR 胎盘中鉴定出 569 个上调基因和 521 个下调基因。差异基因转录在很大程度上与基于 H3K27ac 状态的预期方向相对应。源自高乙酰化位点的上调转录物的途径分析显示，与 HIF-1-α转录因子网络相关的基因和其他几个已知参与胎盘病理学的基因（LEP、FLT1、HK2、ENG、FOS）。在低乙酰化位点附近下调的转录物与免疫系统和生长激素受体信号有关。此外，我们在差异乙酰化区域内发现了 141 个转录因子结合基序的富集。在相应的转录因子中，有四个上调，SP1、ARNT2、HEY2 和 VDR，两个下调，FOSL 和 NR4A1。
我们证明了全基因组范围内 H3K27ac 的改变在 FGR 胎盘中起关键作用，与与胎盘功能相关区域的转录谱变化相对应。对 H3K27ac 在 FGR 和胎盘-胎儿发育中的作用的进一步研究可能有助于确定这种目前无法治愈的疾病的治疗新靶点。
Zotero 插件
