Vascular lncRNA biology

Until very recently, RNA was believed to function primarily as a messenger of genetic information from DNA to proteins. This notion has changed dramatically as the functional significance of non-coding, or un-translated, RNAs (ncRNAs) has been uncovered.

A very large, yet poorly understood, class of ncRNAs is long non-coding RNA (lncRNA). RNA molecules in this classare broadly defined as being transcribed but not translated and greater than 200nt in length. It has been demonstrated that lncRNAs are physiologically important with very diverse roles in nearly all cellular processes.

Our aims are

We want to understand how lncRNAs can control transcriptional activity through chromatin-remodelling complex recruitment with a focus on the cardiovascular system. Through a systematic understanding of how lncRNAs facilitate chromatin-modifyingcomplex interaction, assembly and recruitment to target sites, we will learn how lncRNAs control gene expression programs important for vascular cell function, physiology and disease development.

Our previous work

We have already demonstrated that lncRNAs are important for endothelial cell function, contribute to nucleosome remodelling and are critical for the control of vascular gene expression programs:

NONHSAT073641 was identified as a pseudogene for PAFAH1B1 (LIS1) maintaining an angiogenic phenotype (Josipovic et al., Acta Physiol (Oxf) 2016).
LISPR1 (Long intergenic noncoding RNA antisense to S1PR1) was identified as being misregulated in cardiovascular disease and acts as a novel regulatory unit for S1PR1 expression and S1P signalling (Josipovic et al., J Mol Cell Cardiol 2018).
MANTIS is induced by laminar flow and statins. It controls angiogenesis and cell adhesion through the chromatin-remodelling protein BRG1. MANTIS gene expression is suppressed by histone demethylase JARID1B and activated by the Krüppel-like transcription factors 2 and 4. It is highly important for the control of the angiogenic gene program and is misregulated in glioblastoma, atherosclerosis and pulmonary hypertension (Leisegang et al., Circulation 2017; Leisegang et al., Eur Heart J 2019).

Our current investigations

We hypothesise that lncRNAs control, address and target the chromatin-remodeling complexes to specific regions in the genome and thereby facilitate execution of different cellular expression programmes. Therefore, we are currently characterizing cell-specific lncRNAs and complete lncRNA-interactomes and their influence on target site recognition of chromatin-remodelling proteins. Next generation sequencing combined with advanced CRISPR tools allow us to determine the role of these lncRNAs in target recruitment, nucleosome remodelling and gene expression control. We also suggest that RNA modifications, structure and DNA architecture are important for target recognition. Mapping RNA-protein sites will reveal active domains important for the plasticity, physiology and function in the vascular system.