Honoratus Van Bakel

Research

De novo reconstruction of transcriptomes

Whole-genome transcriptome profiling has been widely used to assess the cellular state, but the need for reference genome and transcriptome sequences has restricted many of these analyses to well-studied model organisms. More recently, NGS technologies coupled with de novo assembly have made it possible to obtain transcriptome data for organisms that are not experimentally tractable, as well as from complex environments such as the microbial communities that inhabit our skin and gastrointestinal tract. We are using de novo assembly approaches to reconstruct the metabolic state of human microbial communities and how changes in this metabolism affect the host. In addition, we are reconstructing transcriptional regulatory networks in medicinal plants with the aim of increasing the production of medicinal compounds and enhancing their potential to treat disease.

Regulation of alternative splicing

Alternative splicing (AS) is one of the mechanisms by which differentiated, non-dividing, cells can change their proteome composition. Over the past years, rapid developments in NGS have led to the identification of large numbers of AS events for protein coding transcripts in humans and other higher eukaryotes, however, comparatively little is known of how these events are regulated. Errors in RNA splicing, for example through mutations that alter existing splice sites or through the creation of cryptic sites, have been linked to a variety of human diseases. Our lab is developing novel sequencing approaches to identify the key RNA elements and sequence motifs involved in splicing and the regulation of alternative splicing. We also plan to evaluate the functional effects of mutations in these motifs and their implication for disease.

The role of long non-coding RNAs in gene regulatory networks

The RNA ecosystem has significantly expanded in recent years, with the identification of new transcript categories in humans and other eukaryotes that thus far remain largely uncharacterized. These include a class of large intergenic non-coding RNAs (lincRNAs) that can be differentiated from other non-coding RNAs based on their length (~1 kb on average), separation from protein-coding genes, and degree of conservation. Like mRNAs, lincRNAs can undergo splicing and are expressed in tissue-specific patterns. While the vast majority of lincRNAs remain poorly characterized, recent studies of individual cases have implicated them in a variety of cellular functions such as the regulation of chromatin state and gene expression, and highlighted their relevance for disease. Previously, we have identified hundreds of new lincRNA candidates that are transcribed in evolutionary conserved regions in the genome. Current research in the lab is focused on using next-generation sequencing (NGS) technologies such as RNA-Seq, ChIP-Seq and RIP-Seq to elucidate the role of these and other lincRNAs in epigenetic and gene regulatory networks. The results of this research will help guide development of new methodologies to rewire these networks for future therapeutic interventions.