Lin, Chien-Ling
Genome-Wide Analysis of the mRNA Splicing and Translation
Post-transcriptional control is the most important regulation to maximize the genome capacity and to fine-tune the gene expression, and it makes us human so much more sophisticated than others. Transcription is only the initial step of the gene expression. After being transcribed from DNA, the intervening non-coding sequence, introns, will be removed, and the rest, termed exons, will be precisely ligated. This process is pre-mRNA splicing. Pre-mRNA splicing is a highly regulated process with remarkable precision. There are on average about 10 exons per human gene. In human genome, the introns compose about 90% of the gene, with a median size ~1.4 kb. The dinucleotide splice sites (GU for 5' splice site and AG for 3' splice site) need to be accurately recognized in every intron. Moreover, there are usually more than one splicing isoform for a gene. With various combinations of exons and even multiple splice sites per exon, alternative splicing greatly increases the complexity of our genome. Alternative splicing is developmentally regulated and cell type-dependent. The extensive alternative splicing explains why gene numbers do not always correlate with the complexity of an organism. For example, the number of genes encoded in human is slightly less than that in C. elegans, but the human exon number and the complexity of the gene structure far exceed those of C. elegans. However, with such high importance, the mechanism of the splicing regulation is not fully understood. In our lab, with interdisciplinary approaches, we want to study how splicing sites are recognized and how splicing isoforms are determined developmentally in a genome-wide scale.
Following splicing, the mature mRNA is transported to subcellular compartments and awaits proper signals for translation. Before the translational activation, these chemically active RNAs need to be protected to keep its coding content intact and silent. The untranslated regions of mRNA contain many sequence elements that are critical for its stability and translation regulation. Protein factors and/or microRNAs may control RNA activity through binding to these regulatory elements. In the past, RNAs were once thought to be only "messengers" of DNAs, but recent findings revealed that the control of the RNA activity plays an indispensable role in cell fate determination, and its mis-regulation could cause many diseases. Therefore, we are going to investigate if the RNA stability and translation level is affected by the disease-related mutations and single nucleotide polymorphisms (SNPs). Using mass-parallel assays, we will analyze how these mutations and SNPs affect disease status through regulating the RNA activity.
Selected Publications:
- Rachel Soemedi, Kamil J. Cygan, Christy Rhine, David T. Glidden, Allison J. Taggart, Chien-Ling Lin, Alger M. Fredericks, William G. Fairbrother. 2017. The Effects of Structure on pre-mRNA Processing and Stability. Methods in press.
- Allison J Taggart*, Chien-Ling Lin*, Barsha Shrestha, Claire Heintzelman, Seong Won Kim and William G Fairbrother. 2017. Large-scale Analysis of Branchpoint Usage across Species and Cell Lines. Genome Research 27:639-649. (*contributed equally)
- Chien-Ling Lin, Allison J Taggart, William G Fairbrother. 2016. RNA Structure in Splicing: an Evolutionary Perspective. RNA Biol. 13:766-771.
- Yen-Tsung Huang, Su Chu, Eric B Loucks, Chien-Ling Lin, Charles B Eaton, Stephen L Buka and Karl T Kelsey. 2016. Epigenome-wide Profiling of DNA Methylation in Paired Samples of Adipose Tissue and Blood. Epigenetics 11:227-236.
- Chien-Ling Lin*, Allison J Taggart*, Kian Huat Lim*, Kamil J Cygan, Luciana Ferraris, Robbert Creton, Yen-Tsung Huang, and William G Fairbrother. 2016. RNA structure replaces the need for U2AF2 in splicing. Genome Research 26:12-23. (*contributed equally)
- Yen-Tsung Huang, Thomas Hsu, Karl T. Kelsey and Chien-Ling Lin. 2015. Integrative analysis of micro-RNA, gene expression, and survival of glioblastoma multiforme. Genet Epidemiol. 39:134-143.
- Moris Nechama, Chien-Ling Lin and Joel D. Richter. 2013. An unusual two-step control of CPEB destruction by Pin1. Mol Cell Biol. 33: 48-58.
- Chien-Ling Lin, Yen-Tsung Huang and Joel D. Richter. 2012. Transient CPEB Dimerization and Translational Control. RNA 18: 1050-1061.
- Chien-Ling Lin, Veronica Evans, Shihao Shen, Yi Xing and Joel D. Richter. 2010. The nuclear experience of CPEB: implications for RNA processing and translational control. RNA 16: 338-348.