Dynamic Organization of lncRNA and Circular RNA Regulators Collectively Controlled Cardiac Differentiation in Humans

Abstract

Advances in developmental cardiology have increased our understanding of the early aspects of heart differentiation. However, understanding noncoding RNA (ncRNA) transcription and regulation during this process remains elusive. Here, we constructed transcriptomes for both long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) in four important developmental stages ranging from early embryonic to cardiomyocyte based on high-throughput sequencing datasets, which indicate the high stage-specific expression patterns of two ncRNA types. Additionally, higher similarities of samples within each stage were found, highlighting the divergence of samples collected from distinct cardiac developmental stages. Next, we developed a method to identify numerous lncRNA and circRNA regulators whose expression was significantly stage-specific and shifted gradually and continuously during heart differentiation. We inferred that these ncRNAs are important for the stages of cardiac differentiation. Moreover, transcriptional regulation analysis revealed that the expression of stage-specific lncRNAs is controlled by known key stage-specific transcription factors (TFs). In addition, circRNAs exhibited dynamic expression patterns independent from their host genes. Functional enrichment analysis revealed that lncRNAs and circRNAs play critical roles in pathways that are activated specifically during heart differentiation. We further identified candidate TF-ncRNA-gene network modules for each differentiation stage, suggesting the dynamic organization of lncRNAs and circRNAs collectively controlled cardiac differentiation, which may cause heart-related diseases when defective. Our study provides a foundation for understanding the dynamic regulation of ncRNA transcriptomes during heart differentiation and identifies the dynamic organization of novel key lncRNAs and circRNAs to collectively control cardiac differentiation.

MIR22HG acts as a tumor suppressor via TGFβ/SMAD signaling and facilitates immunotherapy in colorectal cancer

“…With the development of next-generation sequencing technology, it is realized that the most part of human genome is transcribed to noncoding RNAs [2]. Of these newly discovered RNA regulatory elements, long noncoding RNAs (lncRNAs) have been demonstrated to play critical roles in diverse cellular processes [3][4][5]. LncRNAs can serve as signal mediators, scaffold or molecular decoys to function in epigenetic, transcriptional and posttranscriptional regulation.…”

Circular RNA in cardiovascular disease

“…These characteristics may place circRNA at the forefront of potential candidates for diagnostic and prognostic biomarkers for diseases, and especially since circRNA is present in the plasma (Salgado‐Somoza, Zhang, Vausort, & Devaux, ). circRNAs often exhibit cell type, tissue, and developmental stage‐specific expression in organisms (Jakobi, Czaja‐Hasse, Reinhardt, & Dieterich, ; Li et al, ; Memczak et al, ; Xu et al, ). The expression profiles of circRNA were different at four heart differentiation stages: undifferentiated, mesoderm, cardiac progenitor, and definitive cardiomyocytes (Li et al, ). Werfel et al observed significantly higher overall circRNA expression in rat neonatal hearts compared with adult rat hearts (Werfel et al, ); and remarkable changes in circRNA expression were also observed amongst different stages of induced pluripotent stem cell‐derived cardiomyocytes (Siede et al, ). circRNAs seem to be evolutionarily conserved as evident by their homologous sequences across species (Jeck et al, ).…”

Effect of eleutheroside B1 on non‑coding RNAs and protein profiles of influenza A virus‑infected A549 cells

“…There is increasing evidence to indicate the functional involvement of these regulatory miRNAs, vault complex-associated RNAs (vtRNAs) and lncRNAs in influenza virus replication (21,22). For example, some studies have demonstrated that ncRNAs can regulate the activation of pattern recognition receptor (PRR)-associated signaling and transcription factors, as well as the production of interferons (IFNs) and the expression of critical IFN-stimulated genes (ISGs) (23,24). In addition to these ncRNAs, circular RNAs (circRNAs) are a novel type of RNA that, unlike linear RNAs, form a covalently closed continuous loop, and are highly represented in the eukaryotic transcriptome (25,26).…”