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Circular RNAs (circRNAs) are covalently closed, endogenous biomolecules in eukaryotes with tissue-specific and cell-specific expression patterns, whose biogenesis is regulated by specific cis-acting elements and trans-acting factors. Some circRNAs are abundant and evolutionarily conserved, and many circRNAs exert important biological functions by acting as microRNA or protein inhibitors ('sponges'), by regulating protein function or by being translated themselves. Furthermore, circRNAs have been implicated in diseases such as diabetes mellitus, neurological disorders, cardiovascular diseases and cancer. Although the circular nature of these transcripts makes their detection, quantification and functional characterization challenging, recent advances in high-throughput RNA sequencing and circRNA-specific computational tools have driven the development of state-of-the-art approaches for their identification, and novel approaches to functional characterization are emerging.

The biogenesis, biology and characterization of circular RNAs.

circRNA Biogenesis Competes with Pre-mRNA Splicing

Noncoding RNAs (ncRNAs) have numerous roles in development and disease, and one of the prominent roles is to regulate gene expression A vast number of circular RNAs (circRNAs) have been identified, and some have been shown to function as microRNA sponges in animal cells Here, we report a class of circRNAs associated with RNA polymerase II in human cells In these circRNAs, exons are circularized with introns 'retained' between exons; we term them exon-intron circRNAs or EIciRNAs EIciRNAs predominantly localize in the nucleus, interact with U1 snRNP and promote transcription of their parental genes Our findings reveal a new role for circRNAs in regulating gene expression in the nucleus, in which EIciRNAs enhance the expression of their parental genes in cis, and highlight a regulatory strategy for transcriptional control via specific RNA-RNA interaction between U1 snRNA and EIciRNAs

Exon-intron circular RNAs regulate transcription in the nucleus

Circular RNA transcripts were first identified in the early 1990s but knowledge of these species has remained limited, as their study through traditional methods of RNA analysis has been difficult Now, novel bioinformatic approaches coupled with biochemical enrichment strategies and deep sequencing have allowed comprehensive studies of circular RNA species Recent studies have revealed thousands of endogenous circular RNAs in mammalian cells, some of which are highly abundant and evolutionarily conserved Evidence is emerging that some circRNAs might regulate microRNA (miRNA) function, and roles in transcriptional control have also been suggested Therefore, study of this class of noncoding RNAs has potential implications for therapeutic and research applications We believe the key future challenge for the field will be to understand the regulation and function of these unusual molecules

Detecting and characterizing circular RNAs

Thousands of loci in the human and mouse genomes give rise to circular RNA transcripts; at many of these loci, the predominant RNA isoform is a circle. Using an improved computational approach for circular RNA identification, we found widespread circular RNA expression in Drosophila melanogaster and estimate that in humans, circular RNA may account for 1% as many molecules as poly(A) RNA. Analysis of data from the ENCODE consortium revealed that the repertoire of genes expressing circular RNA, the ratio of circular to linear transcripts for each gene, and even the pattern of splice isoforms of circular RNAs from each gene were cell-type specific. These results suggest that biogenesis of circular RNA is an integral, conserved, and regulated feature of the gene expression program.

/pdf/cell-type-specific-features-of-circular-rna-expression-4ao4gawmcm.pdf

Cell-type specific features of circular RNA expression.

Function and regulation in MAPK signaling pathways: Lessons learned from the yeast Saccharomyces cerevisiae

Patrick O Brown should also be listed as a corresponding author. His email address is pbrown@stanford.edu

Correction: Cell-Type Specific Features of Circular RNA Expression

Elevated external solute stimulates a conserved MAPK cascade that elicits responses that maintain osmotic balance. The yeast high-osmolarity glycerol (HOG) pathway activates Hog1 MAPK (mammalian ortholog p38α/SAPKα), which enters the nucleus and induces expression of >50 genes, implying that transcriptional up-regulation is necessary to cope with hyperosmotic stress. Contrary to this expectation, we show here that cells lacking the karyopherin required for Hog1 nuclear import or in which Hog1 is anchored at the plasma membrane (or both) can withstand long-term hyperosmotic challenge by ionic and nonionic solutes without exhibiting the normal change in transcriptional program (comparable with hog1Δ cells), as judged by mRNA hybridization and microarray analysis. For such cells to survive hyperosmotic stress, systematic genetic analysis ruled out the need for any Hog1-dependent transcription factor, the Hog1-activated MAPKAP kinases, or ion, glycerol, and water channels. By contrast, enzymes needed for glycerol production were essential for viability. Thus, control of intracellular glycerol formation by Hog1 is critical for maintenance of osmotic balance but not transcriptional induction of any gene.

https://www.pnas.org/content/pnas/105/34/12212.full.pdf

Stress resistance and signal fidelity independent of nuclear MAPK function

Mitotic yeast (Saccharomyces cerevisiae) cells express five related septins (Cdc3, Cdc10, Cdc11, Cdc12, and Shs1) that form a cortical filamentous collar at the mother-bud neck necessary for normal morphogenesis and cytokinesis. All five possess an N-terminal GTPase domain and, except for Cdc10, a C-terminal extension (CTE) containing a predicted coiled coil. Here, we show that the CTEs of Cdc3 and Cdc12 are essential for their association and for the function of both septins in vivo. Cdc10 interacts with a Cdc3–Cdc12 complex independently of the CTE of either protein. In contrast to Cdc3 and Cdc12, the Cdc11 CTE, which recruits the nonessential septin Shs1, is dispensable for its function in vivo. In addition, Cdc11 forms a stoichiometric complex with Cdc12, independent of its CTE. Reconstitution of various multiseptin complexes and electron microscopic analysis reveal that Cdc3, Cdc11, and Cdc12 are all necessary and sufficient for septin filament formation, and presence of Cdc10 causes filament pairing. These data provide novel insights about the connectivity among the five individual septins in functional septin heteropentamers and the organization of septin filaments.

/pdf/protein-protein-interactions-governing-septin-heteropentamer-sy6r9furd4.pdf

Raymond E. Chen

Papers

Cell-type specific features of circular RNA expression.

Function and regulation in MAPK signaling pathways: Lessons learned from the yeast Saccharomyces cerevisiae

Correction: Cell-Type Specific Features of Circular RNA Expression

Stress resistance and signal fidelity independent of nuclear MAPK function

Protein–Protein Interactions Governing Septin Heteropentamer Assembly and Septin Filament Organization in Saccharomyces cerevisiae