About Us

About the PI:

I am an Associate Professor of the Aab Cardiovascular Research Institute (CVRI) of the University of Rochester School of Medicine and Dentistry. I am a primary faculty member of the Department of Medicine and a secondary faculty member of the Department of Biochemistry & Biophysics. I am also a member of the Center for RNA Biology (from Genome to Therapeutics) and the Center for Biomedical Informatics. 

As an early career investigator, my research focuses on the pathophysiological function and molecular mechanism of non-coding RNAs and translational control in cardiac health and disease. During my B.S. research at Wuhan University (Upenn in China), I studied the mechanism of group I intron self-cleavage (ribozyme). During graduate research, I focused on the structural and functional studies of transfer RNA (tRNA) and aminoacyl-tRNA synthetase. I studied the structure and function of leucyl-tRNA synthetase from bacteria, yeast, and human under the guidance of Dr. En-Duo Wang (Chinese Academy of Sciences member). I anticipated the development of a topical antifungal medication for the treatment of onychomycosis, namely, leucyl-tRNA synthetase inhibitor (Tavaborole, AN2690, trade name Kerydin). Tavaborole began its Phase 3 trials in December 2010 and was approved by the US FDA in July 2014 (en.wikipedia.org/wiki/Tavaborole). My post-doctoral training under the tutelage of Prof. Paul L. Fox (Cleveland Clinic, Endowed Chair of Inflammation and Angiogenesis and a pioneer in the area of 3'UTR-mediated translational regulation in inflammation and angiogenesis) has provided me with the expertise, leadership, broad background, and in-depth experience necessary for our research program. I have been working on gene regulation of VEGFA (vascular endothelial growth factor A, a major cytokine required for heart development and cardiac repair) in the human inflammatory process for 8 years using a variety of molecular and cellular, biochemical, and genetic approaches. I have discovered that coding-region polyadenylation generates a truncated human aminoacyl-tRNA synthetase. This tRNA synthetase variant functions to oppose transcript-specific translational repression in human monocytes/macrophages to regulate VEGFA expression and inflammatory responses. We published these findings of novel mRNA processing and translational control mechanisms in Cell 2012. Around the same time, I have elucidated the mechanism by which an RNA binding protein, hnRNP L (heterogeneous nuclear ribonucleoprotein L), regulates the translation of VEGFA and other mRNAs (a founding member of vertebrate stress-responsive protein-directed RNA switch pathway, a homolog of bacteria riboswitch in human) under hypoxic and inflammatory stress in myeloid cells. These results were published in PLOS Biology in 2013. My AHA SDG-supported research project focuses on regulating the VEGFA RNA switch pathway. I have discovered that miR-574-3p negatively regulates the VEGFA RNA switch in monocytes and antagonizes tumorigenesis via direct binding of hnRNP L based on a molecular “decoy” mechanism. These findings were recently published in Nucleic Acids Research (IF=19.16) in May 2017. My lab has established an independent research program to investigate the cardioprotective function and molecular mechanisms of mammalian non-coding RNAs (miRNA, riboswitch, 3'UTR) in cardiac hypertrophy and pathological remodeling. We laid the groundwork for the proposed research by developing a number of genetic knockout mouse models and establishing a comprehensive series of assays (ribosome profiling or Ribo-seq, RiboTag-seq, polysome profiling-seq for translation state analysis, CLIP-seq and RIP-seq for RBP-RNA interaction mapping, CRISPR-Cas9 for genome editing, protein expression and purification in bacteria for biochemical assays, techniques to isolate and culture primary myocytes and fibroblasts, etc.). The surgical Core facility from Aab CVRI will provide strong technical support for experimental heart failure models (e.g., ISO infusion, TAC, LAD ligation, etc.) and echocardiography.


On Sep. 1st 2016, I started my independent laboratory in Aab CVRI of URMC. During 2016-2017, my lab established an independent research program to systematically investigate the RNA- and RBP-based translational control mechanisms in cardiac biology and heart disease. Inspired by the amazing discoveries of miRNA and ribosome highlighted by the 2008 Albert Lasker Award for Basic Medical Research and the 2009 Nobel Prize in Chemistry, respectively, I consolidated my belief in studying translational control mechanisms mediated by noncoding RNAs, RNA-binding protein, and regulation of ribosome activity in the cardiovascular system that I immersed myself for a long period.

The first research program I took at the beginning of my independent work was to study the cardioprotective function and molecular mechanisms of mammalian miR-574 (including guide and passenger strands miR-574-5p and miR-574-3p) in cardiac hypertrophy and pathological remodeling. This project has been supported by an R56 and an R01 grant from NHLBI starting in 2016 and 2018, respectively. In this research program, we discovered that dual-strand miRNAs miR-574-5p and miR-574-3p are induced in human and mouse failing hearts compared to healthy hearts. Using the miR-574 genetic knockout mouse model and next-generation deep sequencing technique, we found that miR-574-5p and miR-574-3p target a potential translational control factor in mitochondria, FAM210A (family with sequence similarity 210 member A) in cardiac myocytes and fibroblasts, thereby maintaining mitochondrial homeostasis and preventing cardiac hypertrophy and ventricular remodeling. This work demonstrates that the miR-574-FAM210A axis regulates mitochondrial translation to maintain the optimal expression of mitochondrial electron transport chain complex genes. More importantly, miR-574 delivered in the heart failure mouse models via nanoparticles can be a potential therapeutic to antagonize cardiac pathological remodeling. Based on these findings, I have proposed an innovative concept of “normalizing” mitochondrial translation to maintain the homeostatic balance with cytosolic translation to protect the heart from progressive pathological remodeling and heart failure. The manuscript of this work was recently published in EMBO Molecular Medicine (IF: 14). Translational regulation inside mitochondria is still underexplored, and more research needs to be performed in this area to discover novel therapeutic targets in the translational process to treat mitochondrial diseases. Recently, our prepared manuscript showed that Fam210a cardiomyocyte-specific genetic knockout mouse model exhibited progressive mitochondrial cardiomyopathy and heart failure. Multi-omics analyses revealed chronic activation of an evolutionarily conserved central translational control pathway, namely, integrated stress response (ISR) in Fam210a knockout hearts. We are studying how mitochondrial stress activates the ISR in mouse models of mitochondrial cardiomyopathy using ribosome profiling (Ribo-seq). I will expand this research program to further elucidate the functional and mechanistic relationship among translational control, mitochondrial biology, and heart disease, aiming to manipulate translation pathways to treat cardiac disorders.

Around the same time, I developed an exciting research project addressing a long-standing scientific question about what mediates translational control of pro-fibrotic protein synthesis during cardiac fibrosis and how it is achieved. I started with understanding the function and mechanism of EPRS in the translational regulation of cardiac fibrosis. We received a second R01 grant in 2019 to support this work. We discovered that multiple cardiac stresses induce EPRS that promotes cardiac fibrosis via increased Pro-tRNAPro pool and consequent stabilization and translation of pro-fibrotic proline codon-rich mRNAs (e.g., collagens, among others) in cardiac fibroblasts. Phenotypic studies in Eprs global and myofibroblast-specific conditional knockout mouse models showed that reducing EPRS protein level significantly compromise cardiac fibrosis in multiple heart failure mouse models (e.g., neurohumoral stimulation, pressure overload, and myocardial infarction). Using a pharmacological EPRS inhibitor halofuginone combined with transcriptomic and translatomic (RNA-Seq and polysome-Seq) profiling, we discovered transcriptome-wide EPRS preferential target mRNAs. SULF1 was confirmed as a novel myofibroblast activation marker and anti-fibrosis target among these targets. This research program provides novel insights into the translational control mechanisms in cardiac fibrosis. It will promote the development of novel therapeutic approaches (e.g., inhibiting translation factors) based on h gene translation to treat cardiac fibrosis. The manuscript of this work was published in Circulation Research (IF: 23.21). This is a starting point for understanding translational control during cardiac fibrosis. During the next 5-10 years, we will further study the role of translation factors in regulating fibrogenesis in the heart. 

              I have been supervising five post-doctoral fellows. Dr. Jiangbin Wu was promoted to Research Assistant Professor and obtained his AHA CDA grant in 2021, he is joining Soochow University to become an independent Professor in June 2023. Dr. Chinna Kadiam was promoted to Staff Scientist in 2021 and joined Scriptr Global company to study genome editing and develop novel circRNA therapeutics to treat human genetic diseases. Eng-Soon Khor is joining a university at Malysia to open his independent lab soon. I also mentor three graduate students (Omar Hedaya, Lindsey Wainwright, and Feng Jiang) and two undergraduate students (Matthew Auguste and Emily Bonanno). My long-term research goal is to understand the translational control process and underlying mechanisms in the cardiac system and heart disease and develop novel therapeutic approaches for treating heart disease by targeting protein translation.

        After promotion to Associate Professor with limited tenure in 2021, I expanded my research on translational regulation of gene expression in cardiomyocyte hypertrophy and cardiac fibroblast activation during cardiac pathological remodeling and fibrosis. Accumulating evidence suggests that posttranscriptional control of gene expression, including RNA splicing, transport, modification, translation, and degradation, primarily relies on RNA binding proteins (RBPs). However, the functions of many RBPs remain understudied. We have recently characterized the function of a novel RBP, Proline-Rich Coiled-coil 2B (PRRC2B). Through photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation and sequencing (PAR-CLIP-seq), we identified transcriptome-wide CU- or GA-rich PRRC2B binding sites near the translation initiation codon on a specific cohort of mRNAs in HEK293T cells. These mRNAs, including oncogenes and cell cycle regulators, exhibited decreased translation upon PRRC2B knockdown, as revealed by polysome-associated RNA-seq, resulting in reduced G1/S phase transition and cell proliferation. Antisense oligonucleotides blocking PRRC2B interactions with CCND2 mRNA decreased its translation, thus inhibiting G1/S transition and cell proliferation. Mechanistically, PRRC2B interactome analysis revealed RNA-independent interactions with eukaryotic translation initiation factors 3 (eIF3) and 4G2 (eIF4G2). The interaction with translation initiation factors is essential for PRRC2B function since the eIF3/eIF4G2-interacting defective mutant, unlike wild-type PRRC2B, failed to rescue the translation deficiency or cell proliferation inhibition caused by PRRC2B knockdown. We recently published this work in Nucleic Acids Research. We are working on generalizing the idea that PRRC2B may be essential for efficiently translating specific cell cycle and protein homeostasis-related proteins and regulating cell proliferation or viability in other cancer cells.

              Short peptide-encoding sequences in the 5' untranslated region of messenger ribonucleic acids (mRNA), called upstream open reading frames (uORFs), are widespread in ~50% of human mRNAs. Translating these uORF sequences reduces the protein output of an mRNA main open reading frame (mORF). Our bioinformatic analysis of human and mouse ribosome profiling databases uncovered a group of cardiac mRNA transcripts containing translated uORFs, such as transcription factors, including GATA4. Biochemical analysis suggests that stabilizing the double-stranded RNA (dsRNA) structure downstream of the start codons of these peptide-encoding sequences enhances their translation, thereby inhibiting the translation of mORFs. This translational inhibitory mechanism is mitigated by DEAD-box RNA helicase DDX3X that unwinds dsRNA and inactivates uORF. Genetic depletion of GATA4 uORF activity using CRISPR-Cas9 mediated genomic editing of the start codon in human embryonic stem cells (ESC) provides evidence of uORF-mediated regulation of mORF translation and cardiomyocyte (CM) hypertrophy (Under preparation for submission). In addition, an established CRISPR-Cas9-derived uORF start codon mutant knock-in mouse model shows spontaneous cardiac hypertrophy and will be used to characterize CM hypertrophy at baseline and under stress conditions. Based on our discovered molecular mechanism of DDX3X-regulated, dsRNA-dependent, uORF-mediated translational inhibition of mORF, we have developed two types of antisense oligonucleotides (ASOs) that can either enhance or reduce uORF translation by strengthening or disrupting dsRNA structures. The uORF-enhancing ASO locks the dsRNA structure and activates translation of the uORF, thereby reducing GATA4 mORF protein expression in human CMs. Treatment of mouse cardiomyopathy models with uORF-enhancing ASO reduces GATA4 protein expression, antagonizes cardiac hypertrophy, and restores cardiac function. Our findings conclude that the cardiac transcription factor mRNA uORF-dsRNA element acts as a switch for translational control of mORF, regulating cardiac hypertrophy, and can be targeted by ASOs to modulate mORF protein translation and cardiac hypertrophy. These findings were recently published in Nature Communications. We will elucidate mRNA structural elements and their interplay with the uORF or other 5' UTR RNA elements for regulating mORF translation and further determine the biological role of the GATA4 uORF in genetic knock-in mouse models and primary CM cell culture systems. These studies will provide novel insights into translational control mechanisms in cardiac biology. This project will promote novel therapeutic approaches (targeting uORF-dsRNA elements) to regulate cardiac hypertrophy. Our mechanism-based design of translation-manipulating ASOs can serve as a proof-of-concept model to apply to different pathogenic mRNA targets.

           As a Department of Medicine, Department of Biochemistry & Biophysics, and Biochemistry & Molecular Biology (BMB) Graduate Program Faculty, I have co-organized Rustbelt RNA Meeting (RRM) in the years 2018 and 2019 as co-vice Chair and co-chair (see https://www.urmc.rochester.edu/biochemistry-biophysics/news.aspx?start=01-01-2019&end=12-31-2019). The RRM2019 conference, with approximately 400 attendees, was held on Oct. 25th & 26th, 2019, at Case Western University and featured 25 speakers. I proposed a workshop for the RRM2019 and invited Dr. Mitch O’Connell to present on "Using CRISPR-Cas13 to target and detect RNA". I also advertised around UofR and had talk or posters presented by members from the laboratories of Drs. Charles Thornton, Dragony Fu, and myself. My graduate students from BMB, Omar Hedaya and Feng Jiang, helped design and construct the meeting booklet and organize the meeting. The University of Rochester Center for RNA Biology and the Department of Biochemistry and Biophysics supported the meeting, among 19 other universities and departments, 10 industrial vendors, and 5 journals/societies. This scholarly contribution significantly enhances the impact of the RNA Center of URMC around northeast America and promotes communications among RNA biologists in the area.  

Most recent research advances in the pharmaceutical industry demonstrate that messenger RNA (mRNA) and its translation have become attractive therapeutic targets for treating human diseases. With the tremendous advancement of RNA technology and FDA-approved RNA-based therapeutics (e.g., siRNA, antisense oligos, COVID19-specific mRNA vaccine, etc.), I believe that it is promising to utilize the knowledge of RNA biology and translational control to develop novel therapeutics for the treatment of cardiovascular disorders among many other human diseases. We recently got funding from Empire Discovery Institute and Novo Nordisk from Denmark to develop novel RNA-based therapeutics to treat human organ fibrosis-related diseases. I have received four NIH R01 grants over the last 7 years. We are also funded by the University Research Award and the Geneen Foundation Award. I will strive to achieve my short- and long-term research goals during my career development and fulfill the mission of the American Heart Association, that is, to be a relentless force for a world of longer, healthier lives.


20 Yao lab tips:

On research and experiments (From my mentor Dr. Paul Fox):

On papers, grants, and presentations  (From my mentor Dr. Paul Fox):

9. Tell a story. We’ve all heard stories from the age of two. We learn from stories and remember them. We love stories.

On manuscripts  (From my mentor Dr. Paul Fox):

10. Look up impact factor of your target journal. That’s how many times you should rewrite the abstract.

11. If the data are beautiful, you can publish them in a journal one tier better than they deserve on their merit. The converse is true for unattractive data.

On grants  (From my mentor Dr. Paul Fox):

12. When preparing a grant proposal, keep in mind that the reviewer starts out mad at you for taking valuable time from something they actually care about.

13. Rewrite the “Specific Aims” page until it sings. The reviewer’s decision is 90% made by the end of this page.

On presentations:

14. To test slide readability, lean far back from your computer screen and squint hard. If you can’t read it, neither can your audience  (From Paul Fox).

15. Keep a “zone of safety” around you, i.e., don’t talk at the limits of your knowledge. Know more than you show (from Don Zilversmit).

On projects:

16. When stumped by a problem, look at it backwards, inside-out, and upside down (from Peter Hinkle).

17. Think about your project nearly all the time; in the shower and during very bad seminars are great for new ideas  (From my mentor Dr. Paul Fox).

For PI’s:

18. Give lab workers freedom of thought and as much freedom of direction as they can handle. This will decrease short-term productivity, but will pay dividends long-term  (From my mentor Dr. Paul Fox).

19. Make the lab environment interesting and fun and the key is to keep good work-life balance  (From my mentor Dr. Paul Fox).

For everyone:

20. Never get discouraged (from Nahum Sonenberg).