Turunen Tanja, Hernández de Sande Ana, Pölönen Petri, Heinäniemi Merja
School of Medicine, University of Eastern Finland, Kuopio FI-70200, Finland.
Department of Environmental and Biological Sciences, University of Eastern Finland, Joensuu FI-80101, Finland.
Comput Struct Biotechnol J. 2021 Apr 5;19:1944-1955. doi: 10.1016/j.csbj.2021.03.035. eCollection 2021.
MicroRNAs are key players in gene regulatory networks controlling cell homeostasis. Their altered expression has been previously linked to disease outcomes and microRNAs thus serve as biomarkers for disease diagnostics. However, their synthesis and its transcriptional regulation have been challenging to investigate. In this study, we validated the use of H3K36me3 histone modification for the quantification of microRNA transcription levels using data from the ENCODE Consortium and then applied this approach to provide new insight into the cell-type-specific regulation in tissues, cell line models and cardiac disease. In cardiomyocytes derived from patients suffering from septal defects, carrying a G296S mutation in the transcription factor GATA4, we show that microRNA gene transcription is altered in cardiomyocytes carrying this mutation and coincides with novel super-enhancers formed within regulatory domains defined using chromatin interaction profiles. The most prominently elevated primary transcript encodes for let-7a and miR-100 that may target genes in the Hippo signaling pathway. Collectively, our work presents a methodology to quantify microRNA gene expression using histone marker data and paves the way for functional studies of cell-type-specific transcriptional regulation occurring in disease pathology.
微小RNA是控制细胞内稳态的基因调控网络中的关键参与者。它们表达的改变先前已与疾病结局相关联，因此微小RNA可作为疾病诊断的生物标志物。然而，它们的合成及其转录调控一直是研究的挑战。在本研究中，我们利用来自ENCODE联盟的数据验证了使用H3K36me3组蛋白修饰来定量微小RNA转录水平的方法，然后应用该方法为组织、细胞系模型和心脏病中的细胞类型特异性调控提供新的见解。在患有间隔缺损的患者来源的心肌细胞中，转录因子GATA4存在G296S突变，我们发现携带该突变的心肌细胞中微小RNA基因转录发生改变，并且与使用染色质相互作用图谱定义的调控域内形成的新型超级增强子一致。最显著升高的初级转录本编码let-7a和miR-100，它们可能靶向Hippo信号通路中的基因。总的来说，我们的工作提出了一种使用组蛋白标记数据定量微小RNA基因表达的方法，并为疾病病理学中发生的细胞类型特异性转录调控的功能研究铺平了道路。
