Pre-mRNA cleavage and polyadenylation is employed for 3′ end processing of almost all eukaryotic mRNAs and is coupled to termination of transcription. Over half of the mammalian genes contain multiple cleavage and polyadenylation sites, polyA sites, leading to variable transcripts containing different coding sequences and/or 3′ untranslated regions (3′UTRs). The 3′UTR is a hotbed for cis elements regulating mRNA metabolism, such as localization, stability, and translation. Thus, alternative cleavage and polyadenylation (APA) can have significant impacts on protein sequence and expression.

Our lab has made a number of contributions to the understanding of APA: 1) we reported that over half of the mammalian genes have APA and created a comprehensive database for polyA sites (PolyA_DB); 2) we systematically identified cis elements around mammalian polyA sites and developed a program for polyA site prediction (PolyA_SVM) using the cis elements; 3) we found that APA isoforms are dynamically regulated across human tissues; 4) we found widespread occurrences of intronic polyadenylation, implicating dynamic interplay between splicing and polyadenylation; 4) we reported that transposable elements have a significant impact on polyA site evolution; 5) we discovered that 3′UTRs progressively lengthen in development and cell differentiation, but shorten during reprogramming of cells to induced pluripotent cells; 6) We found that transcriptional activity regulates APA, streamlining gene expression. We are now trying to understand the evolution of APA and address the molecular mechanisms and consequences of APA in development and cancers.

Representative Publications:

• Ji Z*, Luo W*, Li W, Hoque M, Pan Z, Zhao Y, Tian B. (2011). Transcriptional activity regulates alternative cleavage and polyadenylation. Mol Syst Biol. 7:534.
• Nunes NM, Li W, Tian B, Furger A. (2010). A functional human Poly(A) site requires only a potent DSE and an A-rich upstream sequence. EMBO J. 29:1523-36.
• Ji Z*, Lee JY*, Pan Z*, Jiang B, Tian B. (2009). Progressive lengthening of 3' untranslated regions of mRNAs by alternative polyadenylation during mouse embryonic development. Proc. Natl. Acad. Sci. U. S. A. 106:7028-33.
• Lee JY, Ji Z, Tian B. (2008). Phylogenetic analysis of mRNA polyadenylation sites reveals a role of transposable elements in evolution of the 3' end of genes. Nucleic Acids Res. 36:5581-90.
• Tian B, Pan Z, Lee JY (2007). Widespread mRNA polyadenylation events in introns indicate dynamic interplay between polyadenylation and splicing. Genome Res. 17:156-65.
• Cheng Y, Miura RM, Tian B. (2006). Prediction of mRNA polyadenylation sites by support vector machine. Bioinformatics 22:2320-5.
• Zhang H, Lee JY, Tian B. (2005). Biased alternative polyadenylation in human tissues. Genome Biol. 6:R100.
• Hu J, Lutz CS, Wilusz J, Tian B. (2005). Bioinformatic identification of candidate cis-regulatory elements involved in human mRNA polyadenylation. RNA 11:1485-1493.
• Tian B, Hu J, Zhang H, Lutz CS. (2005). A large-scale analysis of mRNA polyadenylation of human and mouse genes. Nucleic Acids Res. 33:201-212.
• Zhang H, Hu J, Recce M, Tian B. (2005). PolyA_DB: a database for mammalian mRNA polyadenylation. Nucleic Acids Res. D116-20.

Cardiac remodeling is alteration of structure and function of the heart in response to hemodynamic changes and/or injuries. The remodeling process frequently involves myocardial hypertrophy, during which cardiac myocytes grow in size. Whereas cardiac remodeling is regarded as an adaptive mechanism in response to pressure/volume overload, prolonged hypertrophy can eventually lead to heart failure, one of the leading causes of death in the world. Studies in the last few decades have elucidated a number of signaling pathways involved in cardiac remodeling, leading to regulation of transcription factors and microRNAs, which further impact expression of downstream genes.

By exon level analysis of short- and long-term cardiac hypertrophy induced by transverse aortic constriction (TAC), we found that alternative splicing (AS) is widespread during remodeling of the heart. Importantly, genes with functions in certain pathways, such as cytoskeleton, extracellular matrix (ECM), ion handling, and cell cycle, are more likely to be regulated by AS during remodeling. Consistently, a group of splicing regulators are significantly regulated. We are now trying to elucidate the mechanisms of AS in cardiac remodeling using computational analyses and experimental assays, focusing on building an AS regulatory network.

Representative Publications:

• Oka S, Alcendor R, Zhai P, Park JY, Shao D, Cho J, Yamamoto T, Tian B, Sadoshima J. (2011). PPARalpha-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway. Cell Metab. 14:598-611.
• Park JY, Li W, Zheng D, Zhai P, Zhao Y, Matsuda T, Vatner SF, Sadoshima J, Tian B. (2011). Comparative analysis of mRNA isoform expression in cardiac hypertrophy and development reveals multiple post-transcriptional regulatory modules. PLoS ONE 6(7): e22391.
• Depre C, Park JY, Shen YT, Zhao X, Qiu H, Yan L, Tian B, Vatner SF, Vatner DE. (2010). Molecular Mechanisms Mediating Preconditioning Following Chronic Ischemia Differ from those in Classical Second Window. Am J Physiol Heart Circ Physiol. 299:H752-62.
• Shen Y-T, Depre C, Yan L, Park JY, Tian B, Jain K, Chen L, Zhang Y, Kudej RK, Zhao X, Sadoshima J, Vatner DE, Vatner SF. (2008). Repetitive Ischemia Induces a Novel Window of Ischemic Preconditioning. Circulation. 118:1961-9.
• Qiu H, Tian B, Resuello RG, Natividad FF, Peppas A, Shen Y-T, Vatner DE, Vatner SF, Depre C. (2007). Gender-specific regulation of gene expression in the aging monkey aorta. Physiol. Genomics. 29:169-80.

The mammalian genomes express a large number of long noncoding RNAs (lncRNAs). Only a handful of them, however, have been studied. The known lncRNAs have diverse roles in the cell, mostly in the nucleus, such as chromatin remodeling, transcription, and RNA processing. We are currently examining adipogenesis, which is the process that generates adipocytes from precursor cells. It has many implications for human diseases, such as diabetes and cardiovascular diseases. While regulation of protein-coding genes in adipogenesis has been well studied, the role of lncRNAs is completely unclear.