Bin Tian, Ph.D.

Cleavage and polyadenylation (CPA) is responsible for the 3′ end maturation of almost all protein-coding and long non-coding RNAs in eukaryotic cells. The CPA site, commonly known as polyA site or PAS, also plays a key role in termination of transcription. Over 70-80% of human genes harbor multiple PASs, resulting in expression of mRNA isoforms with different 3′ termini, a phenomenon known as alternative cleavage and polyadenylation (APA). APA isoforms can differ in coding sequences and/or 3’ untranslated regions (3’UTRs). The Tian lab has been using a battery of sequencing tools, based on short-read and long-read sequencing technologies, to comprehensively map PASs across species and understand APA site evolution. They are also using single cell RNA sequencing methods to examine cell type specificity of APA isoform expression under physiological and pathology conditions. Moreover, using these technologies, the Tian lab is addressing how PAS choice is coupled with other events of mRNA biogenesis and processing, such as transcription, splicing and base modifications.  

While most PASs in human genes are located in the last exon, a sizable fraction (~20%) of genes display APA in regions upstream of the last exon. PAS usage upstream of the last exon, which has been named intronic polyadenylation, premature cleavage and polyadenylation or alternative terminal, leads to early transcriptional termination (ETT). While some ETT transcripts encode distinct proteins, the majority of them are unstable in the cell, making ETT a powerful mechanism to effectively inhibit gene expression. As such, regulation of ETT, often involving modulation of splicing and CPA activities as well as transcriptional elongation rate, can have substantial impacts on the gene expression program.  The Tian lab is developing tools to regulate genes through ETT. In addition, they are studying how perturbation of ETT impacts neoantigen expression in cancer cells with the goal of enhancing cancer immunotherapies.

The 3’UTRs of protein-coding transcripts play regulatory roles in mRNA metabolism, including mRNA decay, translation and subcellular localization. Sequence and structural motifs embedded in 3’UTRs contribute to 3’UTR functions through interactions with their cognate RNA binding proteins (RBPs) and microRNAs (miRNAs). The Tian lab recently reported widespread translation-independent endoplasmic reticulum association (TiERA) of mRNAs, in which 3’UTRs play an important role in modulating mRNA interactions with the endomembrane system in the cell. The Tian lab is studying how TiERA could impact cell signaling through localized mRNA translation. In addition, the Tian lab recently reported widespread transcript shortening in secretory cell differentiation. The phenomenon, named secretion-coupled APA (SCAP), was observed in multiple professional secretory cells. They are studying how SCAP perturbation in B cells can alter their differentiation into antibody-producing plasma cells, which are critical for humoral immunity. They are also pursuing novel therapeutics to modulate immune cells and cancer cells that display unique mRNA 3’UTR isoform biogenesis and metabolism.

Small molecule inhibitors of CPA (CPAi) have recently been found to be effective anti-cancer therapeutics.  The Tian lab has revealed multiple mechanisms by which CPAi can impact the transcriptome in a cell, including APA isoform changes and transcriptional readthrough. In addition, they found that cancer cells with a high CPA activity and a high proliferation rate are particularly vulnerable to CPAi, due to replication-transcript conflicts.  They are now developing novel, more potent CPAi compounds through medicinal chemistry and antisense oligonucleotides (ASOs) that are amenable to distinct therapeutic deliveries. In addition, they are studying cancer cell signatures that determine the effectiveness of CPAi in multiple cancer types.