Research Summary
The human genome encodes thousands of circular RNAs (circRNA). CircRNA is a special RNA species which are generated by a unique pre-mRNA processing mechanism called back-splicing. During this process, the 5’ end and the 3’ end of the RNA will be joined head-to-tail covalently, forming a closed loop-shape RNA molecule. This unique feature makes circRNA resistant to exonuclease RNA degradation, which is a major mechanism for degrading RNAs in cells, making circRNA hundreds of times more stable than linear RNAs (eg. mRNA). As rapid degradation of linear RNAs enables cells to quickly react to different cell physiological needs
in time, the high stability feature of circRNA raises some fundamental questions for this unique RNA species – Why do cells need these highly stable circRNAs? How do cells utilize them to regulate cell physiology differently from rapid-degraded linear RNAs?
To answer these questions, the Chen lab utilizes multi-omic and high-throughput screening approaches to systematically investigate the regulation and function of circRNA in cells and develop novel circRNA technologies for translational applications. We aim to uncover (i) genomic elements, RNA structures, and protein components regulating the biogenesis and functions of circRNA, (ii) the molecular mechanism of how circRNAs regulate cell physiology, and (iii) how circRNA dysregulation can lead to disease pathogenesis. By achieving these research aims, we will finally be able to resolve the biggest mystery of circRNA biology – the
functional reasons for circRNA.
The high stability also gives circRNA great translational value for RNA medicine and therapeutics. CircRNA can serve as a protein production platform where it has the same non-integrative advantage as the current linear RNA (mRNA) medicine but provides a more long-lasting effect. The Chen lab also aims to (iv) identify the components and mechanisms regulating circRNA translation. Our long-term goal is to utilize this unique high-stability feature of circRNA to develop novel circRNA technologies to further advance RNA medicine
and therapeutics!
Research Goals
RNA binding proteins (RBPs) play key roles in regulating RNA functions, such as RNA localization, degradation, and translation. However, as most of the studies focus on linear RNAs, the RBPs that regulate circRNA functions remain largely unknown. We aim to use mass spectrometry-based approaches to identify the RBPs that regulate circRNA functions. We will further characterize the role of these RBPs in circRNA functions upon down/upregulating the proteins. The findings can answer the fundamental question that if linear RNAs and circRNAs utilize different elements and mechanisms to regulate their functions. Moreover, characterizing these regulatory components under normal
and disease conditions can provide insights into the clinical implications for circRNA-mediated disease.
circRNA translation is regulated by different mechanisms from linear RNAs under stress conditions. However, the regulatory components and mechanisms remain largely unknown. We aim to identify the circRNA binding proteins (circRBPs) and the circRNA secondary structures that regulate circRNA translation under hypoxia conditions.
We will further utilize hypoxia-induced pulmonary hypertension (PH) as a disease model to uncover how circRNAs dysregulation under hypoxia conditions can lead to PH pathogenesis. The findings can help answer how cells utilize circRNA as an alternative protein production template to adapt to environmental changes and
provide clinical insights into the disease pathogenesis under stress conditions.
Although recent in vivo studies have suggested that circRNA translation is regulated post-transcriptionally in a tissue/cell type-dependent manner, the mechanisms enabling this cell type-dependent control remain unknown. We aim to utilize single-cell RNA sequencing (scRNA-seq) and multi-omic approaches to systematically investigate how the functions of circRNAs are regulated in a cell type-dependent manner. The findings can help build a circRNA toolbox for tunable tissue-specific gene expression to serve as a non-integrative and stable platform for cell type-dependent studies or therapeutic interventions.
