Current Research Topics:
Our laboratory uses genomic, computational and molecular approaches to study gene expression and RNA processing in mammalian genomes. We develop computational and statistical tools for exon-level analysis of mammalian transcriptomes using high-density exon microarray and ultra-deep RNA-sequencing data. We conduct computational and experimental research to elucidate the molecular mechanism and regulatory impact of evolutionary changes in gene expression and RNA processing. We are also studying the role of alternative splicing and microRNAs in human diseases.
(1) Pre-mRNA splicing and alternative splicing
Alternative splicing is a major source of transcript and protein diversity in higher eukaryotes. During the splicing of precursor mRNAs, alternative choices of exons and splice sites can produce different mRNA and protein isoforms from a single gene. In the last decade, genomic data indicate that pre-mRNA alternative splicing is widespread in human and many other genomes. This has fascinating implications for the understanding of gene regulation and many human diseases. We develop bioinformatic tools to discover novel alternative splicing events from sequence and microarray data. We use these data to study pre-mRNA alternative splicing at functional, regulatory and evolutionary levels. We are also interested in the discovery and characterization of disease mutations that disrupt pre-mRNA splicing. .
(2) Bioinformatic tool for exon-level analysis of mammalian transcriptomes.
For a long time, studies of alternative splicing were limited by the lack of high-throughput tools for global profiling of alternatively spliced transcripts. This situation is changing with the development of new transcriptome profiling technologies for splicing analysis. For example, RNA-seq (based on Illumina Solexa sequencing) is emerging as a powerful technology for exon-level expression analysis. By mapping millions of RNA-seq reads to individual transcripts and exons, one can estimate the overall abundance of the mRNA transcripts as well as the splicing levels of individual exons. My laboratory is currently developing computational tools for global analysis of splicing using public and in-house RNA-seq data. We are also developing statistical tools for a next-generation exon array, which has a much higher probe density per exon and also includes multiple probes for splice junctions.
(3) Comparative genomics
Our laboratory has a broad interest in comparative and evolutionary genomics. We study genome evolution using combined genomic, bioinformatic and experimental approaches. We are particularly interested in the evolutionary origin and regulatory impact of species-specific coding and non-coding RNA sequences.
(4) Disease-specific perturbation of splicing regulation
Aberrant alternative splicing is a major cause of human diseases. Defects in global regulators of alternative splicing have been implicated in cancers and a variety of genetic disorders. We are developing methods to construct global splicing regulatory networks from heterogeneous genome, transcriptome and protein-RNA interaction data. In collaboration with clinical colleagues, we are combining genomic, computational and experimental tools to delineate disease-specific perturbation of splicing regulatory networks. Currently, we focus on neurological diseases, muscular dystrophy and birth defects.