The short and long of noncoding sequences in the control of vascular cell phenotypes

Abstract

The two principal cell types of importance for normal vessel wall physiology are smooth muscle cells and endothelial cells. Much progress has been made over the past 20 years in the discovery and function of transcription factors that coordinate proper differentiation of these cells and the maintenance of vascular homeostasis. More recently, the converging fields of bioinformatics, genomics, and next generation sequencing have accelerated discoveries in a number of classes of noncoding sequences, including transcription factor binding sites (TFBS), microRNA genes, and long noncoding RNA genes, each of which mediates vascular cell differentiation through a variety of mechanisms. Alterations in the nucleotide sequence of key TFBS or deviations in transcription of noncoding RNA genes likely have adverse effects on normal vascular cell phenotype and function. Here, the subject of noncoding sequences that influence smooth muscle cell or endothelial cell phenotype will be summarized as will future directions to further advance our understanding of the increasingly complex molecular circuitry governing normal vascular cell differentiation and how such information might be harnessed to combat vascular diseases.

A CRISPR Path to Engineering New Genetic Mouse Models for Cardiovascular Research

“…Inasmuch as lncRNAs exhibit diverse functions in maintaining cellular homeostasis, 2c CRISPR will find increasing utility in deciphering the function of this class of non-coding RNA in the vascular system. 87 In addition to lncRNA genes, microRNAs are also amenable to 2c CRISPR deletion, though none have yet to be edited in the mouse. Interestingly, microRNAs may be found within a host lncRNA so it will be important to try and distinguish the biological significance of each using carefully designed 2c CRISPR editing.…”

MYOSLID Is a Novel Serum Response Factor–Dependent Long Noncoding RNA That Amplifies the Vascular Smooth Muscle Differentiation Program

“…18, 21, 22 In this context, although numerous lncRNAs have been intensively investigated in the stem cell and cancer fields, studies of lncRNA in vascular biology and disease are only beginning to be undertaken. 20, 23 …”

A New Editor of Smooth Muscle Phenotype

“…Notably, Acta2 mRNA levels decreased after PDGF treatment at an even greater rate than with the transcriptional inhibitor Actinomycin D, and nuclear run-on indicated that nascent Acta2 mRNA synthesis did not decrease with PDGF treatment (4). Despite these initial observations, subsequent studies of contractile protein regulation in SMC have been largely at the transcriptional, and more recently, epigenetic levels (5,6). …”

“…This suggests that this editing mechanism could potentially target additional genes that contribute to other aspects of SMC phenotypic switching, including proliferation, migration, and extracellular matrix deposition. miRNAs have also been implicated in regulation of SMC differentiation (6). As miRNA precursors can also undergo editing (7), it will be of interest to determine whether miRNA editing might influence SMC phenotype.…”