Our research
Our lab is interested in all aspects of RNA processing and how they contribute to human health and disease.
To solve these questions, we use a combination of nanopore sequencing, functional genomics, molecular biology, and bioinformatic tools.
Nanopore sequencing
Mammalian pre-mRNAs often measure many kilobases, but until recently it was technically difficult to analyze the maturation of entire transcripts. These challenges can now largely be alleviated with nanopore sequencing, the main workhorse of our lab. In this approach, RNA or DNA pass through a pore in which an electrical current is running. As they make their way through, they induce changes in the current that can be converted to nucleotide signal.
With its long reads and the absence of reverse transcription or PCR, direct RNA nanopore sequencing allows for the detection of many RNA processing events across transcripts. The small size of the nanopore devices enables us to sequence directly in the lab!
Pre-mRNA splicing dynamics across long transcripts
The majority of mammalian genes undergo alternative splicing. These genes also contain many long introns, but pre-mRNA splicing mechanisms are still largely studied for one intron at a time. However, there is increasing evidence that nearby splicing reactions are not independent from one another, and that this connectedness is important for splicing fidelity.
We are interested in understanding how the many splicing reactions that occur along a transcript are coordinated to yield the final mature mRNA. We are studying the order in which introns are removed, how this contributes to alternative splicing regulation, how it impacts retention of specific transcripts on chromatin and how this is regulated by genetic variants. We are also investigating how these processes are modulated in different cellular contexts, such as neuronal and muscle cell differentiation.
Crosstalk between splicing and other RNA processing events
Splicing of pre-mRNAs does not happen in isolation, but is mechanistically and physically coupled to other maturation steps within the same transcript, such as 3’-end processing and RNA modifications. Beyond mRNAs, snRNAs and snoRNAs are small non-coding RNAs that play essential functions in RNA processing. The processing of pre-mRNAs, snRNAs and snoRNAs is functionally and physically connected, but how these events influence one another is poorly understood.
We seek to unravel how the interplay and coordination between distinct RNA processing steps yield the mature transcriptome and how this changes during cell differentiation.
RNA processing in human health and diseases
Regulation of RNA processing plays a crucial role in development and disease. For example, alternative splicing is frequently impacted in diseases ranging from cancer to neurodegenerative disorders, as well as during healthy aging. We are interested in understanding how RNA processing allows the cell to respond to different external cues, how this is affected during aging and associated pathologies, and how splicing can be modulated by therapeutic approaches.