Sriram Kiran, Luo Yingjun, Yuan Dongqiang, Malhi Naseeb Kaur, Tapia Alonso, Samara Vishnu Amaram, Natarajan Rama, Bouman Chen Zhen
Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Duarte, CA, United States.
Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA, United States.
Front Cardiovasc Med. 2022 Jun 28;9:881916. doi: 10.3389/fcvm.2022.881916. eCollection 2022.
Vascular endothelial cells (ECs) play a pivotal role in whole body homeostasis. Recent advances have revealed enhancer-associated long non-coding RNAs (lncRNAs) as essential regulators in EC function. We investigated LINC00607, a super enhancer-derived lncRNA (SE-lncRNA) in human arteries with an emphasis on ECs. Based on public databases and our single cell RNA-sequencing (scRNA-seq) data from human arteries collected from healthy and diabetic donors, we found that LINC00607 is abundantly expressed in the arteries and its level is increased in diabetic humans. Using RNA-sequencing, we characterized the transcriptomes regulated by LINC00607 in ECs and vascular smooth muscle cells (VSMCs) and in basal and diabetic conditions in ECs. Furthermore, through transcriptomic and promoter analysis, we identified c-Myc as an upstream transcription factor of LINC00607. Finally, using scRNA-seq, we demonstrated that modified antisense oligonucleotide inhibitor of LINC00607 can reverse dysfunctional changes induced by high glucose and TNFα in ECs. Collectively, our study demonstrates a multi-pronged approach to characterize LINC00607 in vascular cells and its gene regulatory networks in ECs and VSMCs. Our findings provide new insights into the regulation and function of SE-derived lncRNAs in both vascular homeostasis and dysfunction in a cell-type and context-dependent manner, which could have a significant impact on our understanding of epigenetic regulation implicated in cardiovascular health and diseases like diabetes.
血管内皮细胞（ECs）在全身稳态中起着关键作用。最近的研究进展表明，增强子相关的长链非编码RNA（lncRNAs）是EC功能的重要调节因子。我们研究了LINC00607，一种源自人类动脉超级增强子的lncRNA（SE-lncRNA），重点关注ECs。基于公共数据库以及我们从健康和糖尿病供体收集的人类动脉单细胞RNA测序（scRNA-seq）数据，我们发现LINC00607在动脉中大量表达，且在糖尿病患者中其水平升高。利用RNA测序，我们对ECs和血管平滑肌细胞（VSMCs）中以及ECs基础和糖尿病状态下受LINC00607调控的转录组进行了表征。此外，通过转录组和启动子分析，我们确定c-Myc是LINC00607的上游转录因子。最后，利用scRNA-seq，我们证明LINC00607的修饰反义寡核苷酸抑制剂可以逆转高糖和TNFα诱导的ECs功能失调变化。总的来说，我们的研究展示了一种多管齐下的方法来表征血管细胞中的LINC00607及其在ECs和VSMCs中的基因调控网络。我们的发现为SE衍生的lncRNAs在血管稳态和功能失调中的调控和功能提供了新的见解，以细胞类型和背景依赖的方式，这可能对我们理解涉及心血管健康和糖尿病等疾病的表观遗传调控产生重大影响。
