Liana Lareau

Research

Broadly, I am interested in how RNA adds a layer of complexity to gene expression. When I first learned the central dogma of molecular biology — DNA ⇒ RNA ⇒ protein — RNA seemed like a minor player. In truth, it may be the most dynamic step of the process, and its functions are not limited to passing information from the genome to the ribosome. Biologists have spent decades elucidating the roles of RNA and the processes by which genes are copied into mRNA and then translated into protein. Now, reams of data are becoming available from sequencing projects, microarray experiments, and other high-throughput methods.

My research uses bioinformatics methods to study alternative mRNA splicing, one source of complexity in human gene expression. The prevalence of alternative splicing was a surprising outcome of the human genome sequencing project — almost all human genes can be processed into distinct mRNA isoforms. What is all of this alternative splicing doing?

A few years ago, some of my coworkers in the Brenner group made an interesting discovery: a third of the alternative splicing of human genes leads to mRNAs that are probably degraded by a cellular surveillance pathway called nonsense-mediated mRNA decay (NMD) [1]. Why is so much RNA produced only to be destroyed? Perhaps splicing is a noisy process and NMD cleans up the mistakes, but in some cases, the unproductive splicing may be important for gene expression. Unproductive splicing (that is, coupled alternative splicing and NMD) could allow the cell to 'turn down' expression of a gene after the mRNA has already been transcribed from the genome.

More recently, my labmates and I have shown that a particularly interesting family of splicing factors, the SR proteins, may all be regulated by unproductive splicing [2]. We found that all of the human genes in this family have alternative splice forms that are degraded by NMD. Most of them include an alternative exon that marks the mRNA for decay — we call these 'poison exons' because their only role seems to be to 'kill' the mRNA.

This study connected unexpectedly into another of my research interests, evolutionary genomics. The alternative regions of the SR genes are extremely conserved between human and mouse, more conserved than the protein-coding regions of the same genes. Such high conservation is usually a sign of functional constraints on the sequence, and we're still trying to identify the pressures that have kept these regions remarkably static. All sorts of interesting evolutionary questions have come up in the process.

1. Lewis BP, Green RE, Brenner SE. 2003 Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans. Proc Natl Acad Sci U S A. 100 (1): 189-92.

2. Lareau LF, Inada M, Green RE, Wengrod JC, Brenner SE. 2007. Unproductive splicing of SR genes associated with highly conserved and ultraconserved DNA elements. Nature 446 (7138): 926-9.