Research

We study how dynamic protein–RNA and protein–protein interactions contribute to accurate gene expression.

Figure 1: Left: Single-molecule imaging of spliceosome component SF3B1. Right: Imaging transcription and splicing of a nascent pre-mRNA.


1) Gene Regulation via RNA Processing

Gene expression describes how genetic information stored in DNA is used to create proteins, which carry out most cellular functions. However, among all domains of life (from bacteria to eukaryotes), a protein is not made directly from DNA. Instead, proteins are translated from an RNA template, a short-lived transcript of the DNA sequence, which is subject to extensive regulation. For example, human RNAs contain long stretches of sequences that must be removed ('spliced out') before being translated into a protein.

Central Dogma

Figure 2: A simplified cartoon of gene expression: DNA is transcribed into RNA which is translated into protein. Our lab studies RNA-based gene regulation processes.

2) The Spliceosome

While there are many protein complexes that act on RNA to regulate its function, perhaps none are more central to RNA processing than the spliceosome, which is responsible for identifying and removing non-coding regions of the gene called introns. The spliceosome is a massive complex, consisting of hundreds of proteins that must assemble from scratch during every splicing reaction.

Splicing figure

Figure 3: The spliceosome is a huge complex of proteins and RNAs that cuts out non-coding intronic RNA sequences.

3) Open Questions

Due to its numerous components, the spliceosome has been challenging to study. Despite over 40 years of work, the spliceosome has never been reconstituted from purified proteins. Furthermore, even in extracts, splicing is very slow and correct splicing of introns longer than a few kilobases has not been achieved. Our lab will dissect the temporal regulation of splicing in live cells by combining imaging-based approaches with classical biochemistry and sequencing assays. The unifying motivation is that gene expression is fundamentally regulated by poorly understood kinetic processes. By emphasizing kinetic measurements, we aim to uncover new insight into fundamental splicing mechanisms and potentially offer new angles for therapeutic interventions in diseases driven by splicing defects.