Doctor of Philosophy, California Institute of Technology (2017)
The role of circular RNAs in pulmonary hypertension.
The European respiratory journal
Circular RNAs (CircRNAs) are endogenous, covalently circularized, non-protein-coding RNAs generated from back splicing. Most circRNAs are very stable, highly conserved, and expressed in a tissue-, cell- and developmental stage-specific manner. CircRNAs play a significant role in various biological processes, such as regulation of gene expression and protein translation via sponging of microRNAs and binding with RNA binding proteins. CircRNAs have become a topic of great interest in research due to their close link with the development of various diseases. Their high stability, conservation, and abundance in body fluids make them promising biomarkers for many diseases. A growing body of evidence suggests that aberrant expression of circRNAs and their targets plays a crucial role in pulmonary vascular remodeling and Group 1 pulmonary arterial hypertension (PAH) as well as other forms of pulmonary hypertension (PH) (Group 3 and 4). Here we discuss the roles and molecular mechanisms of circRNAs in the pathogenesis of pulmonary vascular remodeling and PH. We also highlight the therapeutic and biomarker potential of circRNAs in PH.
View details for DOI 10.1183/13993003.00012-2022
View details for PubMedID 35680145
Noncoding RNAs: biology and applications-a Keystone Symposia report.
Annals of the New York Academy of Sciences
The human transcriptome contains many types of noncoding RNAs, which rival the number of protein-coding species. From long noncoding RNAs (lncRNAs) that are over 200 nucleotides long to piwi-interacting RNAs (piRNAs) of only 20 nucleotides, noncoding RNAs play important roles in regulating transcription, epigenetic modifications, translation, and cell signaling. Roles for noncoding RNAs in disease mechanisms are also being uncovered, and several species have been identified as potential drug targets. On May 11-14, 2021, the Keystone eSymposium "Noncoding RNAs: Biology and Applications" brought together researchers working in RNA biology, structure, and technologies to accelerate both the understanding of RNA basic biology and the translation of those findings into clinical applications.
View details for DOI 10.1111/nyas.14713
View details for PubMedID 34791665
Structured elements drive extensive circular RNA translation.
The human genome encodes tens of thousands circular RNAs (circRNAs) with mostly unknown functions. Circular RNAs require internal ribosome entry sites (IRES) if they are to undergo translation without a 5' cap. Here, we develop a high-throughput screen to systematically discover RNA sequences that can direct circRNA translation in human cells. We identify more than 17,000 endogenous and synthetic sequences as candidate circRNA IRES. 18S rRNA complementarity and a structured RNA element positioned on the IRES are important for driving circRNA translation. Ribosome profiling and peptidomic analyses show extensive IRES-ribosome association, hundreds of circRNA-encoded proteins with tissue-specific distribution, and antigen presentation. We find that circFGFR1p, a protein encoded by circFGFR1 that is downregulated in cancer, functions as a negative regulator of FGFR1 oncoprotein to suppress cell growth during stress. Systematic identification of circRNA IRES elements may provide important links among circRNA regulation, biological function, and disease.
View details for DOI 10.1016/j.molcel.2021.07.042
View details for PubMedID 34437836
- Publisher Correction: A protein assembly mediates Xist localization and gene silencing. Nature 2020
A protein assembly mediates Xist localization and gene silencing.
Nuclear compartments have diverse roles in regulating gene expression, yet the molecular forces and components that drive compartment formation remain largely unclear1. The long non-coding RNA Xist establishes an intra-chromosomal compartment by localizing at a high concentration in a territory spatially close to its transcription locus2 and binding diverse proteins3-5 to achieve X-chromosome inactivation (XCI)6,7. The XCI process therefore serves as a paradigm for understanding how RNA-mediated recruitment of various proteins induces a functional compartment. The properties of the inactive X (Xi)-compartment are known to change over time, because after initial Xist spreading and transcriptional shutoff a state is reached in which gene silencing remains stable even if Xist is turned off8. Here we show that the Xist RNA-binding proteins PTBP19, MATR310, TDP-4311 and CELF112 assemble on the multivalent E-repeat element of Xist7 and, via self-aggregation and heterotypic protein-protein interactions, form a condensate1 in the Xi. This condensate is required for gene silencing and for the anchoring of Xist to the Xi territory, and can be sustained in the absence of Xist. Notably, these E-repeat-binding proteins become essential coincident with transition to the Xist-independent XCI phase8, indicating that the condensate seeded by the E-repeat underlies the developmental switch from Xist-dependence to Xist-independence. Taken together, our data show that Xist forms the Xi compartment by seeding a heteromeric condensate that consists of ubiquitous RNA-binding proteins, revealing an unanticipated mechanism for heritable gene silencing.
View details for DOI 10.1038/s41586-020-2703-0
View details for PubMedID 32908311