Our lab studies RNA biology using molecular, biochemical, cellular and computational biology approaches. We are particularly interested in post-transcriptional gene regulation in human disease. Currently, we are investigating mechanisms regulating mRNA fate (such as mRNA turnover, translation and localization at the transcriptome level) and the roles of microRNA (miRNA) in airway inflammation and remodeling.
1. Global regulation of mammalian mRNA fate
Post-translational modifications of general decay factors
Both the stability and translation of mRNAs are affected by deadenylation (i.e., shortening of the mRNA 3’ poly(A) tail), which begins when mRNAs arrive in the cytoplasm. Deadenylation is a rate-limiting step for mRNA decay and translational silencing; thus, it is a critical point for controlling mRNA functions. We currently focus on three key mRNA deadenylation factors, which are all interacting with poly(A)-binding protein (PABP)-interacting proteins via a PAM2 motif, including i) GW182, an effector protein of RISC complex in miRNA-mediated gene silencing, ii) TOB2, an anti-proliferative protein that enhances CCR4-CNOT1 complex-mediated general deadenylation, and iii) PAN3, a regulatory factor of the PAN2-PAN3 deadenylase complex involved in general deadenylation. Recently, we conducted a bioinformatics analysis of human PAM2-containing PABP-interacting proteins and found that the PAM2 motif is generally embedded in an extended intrinsically disordered region (IDR), which is predicted to be a hotspot for protein phosphorylation. We subsequently showed that reversible phosphorylation within the IDRs modulates the interactions between the PAM2-containing protein and PABP, leading to changes in mRNA fate. As over 80% of mammalian mRNA-binding proteins are considered IDR proteins, this line of research provides a new framework for designing future studies to investigate how the many distinct mRNA functions involving IRD-containing RNA-binding proteins may be regulated and coordinated through signaling pathways in eukaryotic cells.
Shortening of mRNA 3’ UTRs via alternative 3’ end processing and polyadenylation (APA)
The 3′UTR of mRNA is a hotspot for cis-regulatory elements, such as miRNA binding sites and AU-rich destabilizing elements that control mRNA localization, stability, and translation. One major means to generate mRNA isoforms containing different lengths of 3’UTR is accomplished through APA. Thus, APA can have significant impacts on gene expression. Over 50% of human genes have multiple polyadenylation signals, thereby increasing the complexity of human mRNA transcriptome. In a recent collaborative study, we identified CFIm25, among 15 cleavage and polyadenylation factors, as a master switch that broadly regulates APA. Applying a regression model on standard RNA-seq data for novel APA events, at least 1,450 genes, representing 11% of significantly expressed mRNA in mammalian cells, with shortened 3′UTRs after CFIm25 knockdown were identified. Importantly, the extensive shortening of 3′UTRs causally leads to enhanced cellular proliferation and tumorigenicity of brain tumor. These results describe the importance of 3′UTR usage in cell growth control and underscore the need for further research into the APA-dependent changes of mRNA fate. Currently, we are employing next-generation sequencing-based approaches, such as RNA-seq, BRIC-seq, and ribosome-profiling, to investigate how APA-elicited global shortening of mRNA 3’ UTR impacts the stability and translation of mRNAs at the transcriptome level and how the changes in mRNA fate may be linked to human disease such as cancer.
2. Roles of post-transcriptional mechanisms in controlling airway inflammation
Epithelial cells of the bronchial airways are directly exposed to the environment and are the first line of defense against airborne particulate matter, allergens and infectious agents. Mounting evidence suggests that bronchial epithelial cells play a pivotal, multifaceted role not only in the maintenance of physico-chemical homoeostasis of the airways but also in the pathogenesis of airway diseases. During allergic airway inflammation, the epithelium is both a source of mediator production as well as a target of remodeling processes. We currently focus on the post-transcriptional mechanisms controlling the inflammatory response of human bronchial epithelial cells—in health and in airway disease —particularly in the context of RNA biology. Our recent work along this line has focused on miRNA, the predominant small regulatory RNA subtype in humans (and in all animals). The study of the roles of small regulatory RNAs in airway inflammation is a relatively new and unexplored research field with much potential. MiRNAs serve fundamental biological functions in all animals studied. Our research aim is to analyze and manipulate these small molecules in order to learn how miRNA biology is altered in inflammatory airway diseases and how miRNAs help control decay and translation of mRNAs coding for, e.g., inflammatory mediators and tissue remodeling factors. We seek both to understand how miRNAs contribute to disease pathogenesis, and as a long-term goal to explore how specially designed RNAs may be applied for therapeutic strategies.
UTHealth Medical School
Department of Biochemistry and Molecular Biology
6431 Fannin Street, MSB 6.184
Houston, Texas 77030
713-500-6068 Direct 713-500-0652 Fax
Ph.D. - Indiana University at Bloomington
Postdoctoral Fellow - Harvard Medical School
Messenger RNA Functions in Cancer and Human Disease
Huang KL, Chadee AB, Chen CY, Zhang Y, Shyu AB.
RNA. 2013 Mar;19(3):295-305. doi: 10.1261/rna.037317.112. Epub 2013 Jan 22.
Chen CY, Shyu AB.
Genes Dev. 2013 May 1;27(9):980-4. doi: 10.1101/gad.219469.113.
Masamha CP, Xia Z, Yang J, Albrecht TR, Li M, Shyu AB#, Li W#, and Wagner EJ#.
Nature. 2014 Jun 19;510(7505):412-6. doi: 10.1038/nature13261. Epub 2014 May 11
(#: co-corresponding authors)
Wiley Interdiscip Rev RNA. 2014 Sep-Oct;5(5):713-22. doi: 10.1002/wrna.1241. Epub 2014 Jun 12
Nucleic Acids Res. 2015 Jul 17. pii: gkv728. [Epub ahead of print]
Masamha CP, Xia Z, Peart N, Collum S, Li W, Wagner EJ, Shyu AB.
RNA. 2016 Jun;22(6):830-8. doi: 10.1261/rna.055939.116. Epub 2016 Apr 19read more
Chen CYA, Chang JT, Ho YF, Shyu AB
Nucleic Acids Res. 2016 May 5;44(8):3772-87. doi: 10.1093/nar/gkw205. Epub 2016 Mar 28