Brain cytoplasmic RNA 1 suppresses smooth muscle differentiation and vascular development in mice

Abstract

The cardiovascular system develops during the early stages of embryogenesis, and differentiation of smooth muscle cells (SMCs) is essential for that process. SMC differentiation is critically regulated by transforming growth factor (TGF)-β/SMAD family member 3 (SMAD3) signaling, but other regulators may also play a role. For example, long noncoding RNAs (lncRNAs) regulate various cellular activities and events, such as proliferation, differentiation, and apoptosis. However, whether long noncoding RNAs also regulate SMC differentiation remains largely unknown. Here, using the murine cell line C3H10T1/2, we found that brain cytoplasmic RNA 1 (BC1) is an important regulator of SMC differentiation. BC1 overexpression suppressed, whereas BC1 knockdown promoted, TGF-β-induced SMC differentiation, as indicated by altered cell morphology and expression of multiple SMC markers, including smooth muscle α-actin (αSMA), calponin, and smooth muscle 22α (SM22α). BC1 appeared to block SMAD3 activity and inhibit SMC marker gene transcription. Mechanistically, BC1 bound to SMAD3 via RNA SMAD-binding elements (rSBEs) and thus impeded TGF-β-induced SMAD3 translocation to the nucleus. This prevented SMAD3 from binding to SBEs in SMC marker gene promoters, an essential event in SMC marker transcription. , BC1 overexpression in mouse embryos impaired vascular SMC differentiation, leading to structural defects in the artery wall, such as random breaks in the elastic lamina, abnormal collagen deposition on SM fibers, and disorganized extracellular matrix proteins in the media of the neonatal aorta. Our results suggest that BC1 is a suppressor of SMC differentiation during vascular development.

Fetal Cerebral Circulation as Target of Maternal Alcohol Consumption

“…All in all, angiogenesis is orchestrated by a wide variety of structural and signaling molecules from different families. They include, but are not limited to, vascular endothelial growth factor (VEGF), integrins, fibronectin, vascular cell adhesion molecules, angiopoietins, tyrosine kinases TIE1 and TIE2/TEK, fibroblast growth factors, extracellular matrix proteins and proteinases, Wnt, and transforming growth factor-β signaling (Carmeliet and Collen, 1998; Ulrich et al, 2016; Wang et al, 2018). Vascular development also requires proper stop signals that may act by mere inhibition of angiogenesis-stimulating factors or by induction of vascular regressions, such as via tumor necrosis factor (TNF) signaling and apoptosis (Carmeliet and Collen, 1998).…”

Glycoprotein M6B Interacts with TβRI to Activate TGF-β-Smad2/3 Signaling and Promote Smooth Muscle Cell Differentiation

“…Estrogen receptor‐α (ERalpha) also reduces the SMC‐specific marker expression by inhibition of Smad2 phosphorylation . DeltaEF1, lncRNA growth arrest‐specific 5 (GAS5), and brain cytoplasmic RNA 1 (BC1) can specifically bind to Smad3 protein and reduce Smad3 translocation to the nucleus or bind to TGF‐β‐responsive SMC gene promoters . In addition, miRNA‐503 induces SMC differentiation through TGF‐β signaling by inhibition of Smad7 transcription .…”

Long non-coding RNA Irm enhances myogenic differentiation by interacting with MEF2D

“…Recently, emerging reports are beginning to identify lncRNAs that regulate myogenesis, such as H19 26 , BC1 27 , and MYOSLID 28 . LncRNA Irm was previously identified as an alternatively splicing isoform of Rian gene 4 .…”