Welcome to the RNA networks lab
RNA is a multitalented molecule: it can store genetic information as well as catalyse chemical reactions. According to the RNA world hypothesis, these talents stem from the central role of RNA at the origin of life. In ‘modern’ cells, RNA molecules carry genetic information from DNA to proteins, and in addition they form wonderfully intricate networks of interactions with proteins and other molecules.
We study how RNA networks direct the workings of a cell by regulating gene expression and protein homeostasis. RNAs are coated by proteins to form ribonucleoprotein complexes (RNPs). These proteins guide the RNA on its journey through the cell to regulate gene expression, while the RNAs also regulate the functions of bound proteins and thereby affect their homeostasis. To understand these RNA networks, we develop new techniques that reveal protein-RNA and RNA-RNA interactions within cells and interrogate their functions.
In particular, we investigate how RNPs contribute to the functions of nerve cells in development, how they help us understand brain evolution, and how faulty RNPs lead to conditions affecting the nervous system, particularly neurodegenerative diseases such as amyotrophic lateral sclerosis. We hope our discoveries will open opportunities for new therapies for these diseases.
Dementia Research Institute at King's
We are currently part of the Department of Neuromuscular Diseases at the UCL Queen Square Institute of Neurology, and in April 2022 we will join the Dementia Research Institute at King's College London.
Francis Crick Institute London
Ule Lab is seconded to the Francis Crick Institute until Feb 2025
Hallegger et al, TDP-43 condensation properties specify its RNA-binding and regulatory repertoire Cell. 2021 Sep 2;184(18).
Many neurodegenerative diseases are associated with formation of toxic aggregates of TDP-43, which result from the strong propensity of TDP-43 for molecular condensation. We addressed the long-standing question of whether TDP-43 condensation is required for its RNA binding specificity and function. We created variants of TDP-43 with a gradient of condensation properties as evident by in vitro phase separation, and by imaging the condensates of TDP-43 in cells. We then used comparative iCLIP to find that the condensation of TDP-43 is required for its efficient binding to long RNA regions with widely dispersed binding motifs, which we refer to as ‘binding region condensates’. Thereby, TDP-43 regulates a select subset of 3’UTR isoforms, including autoregulation of TDP-43 itself. Our study thus shows that changes in TDP-43 condensation can deregulate a selective subset of RNAs, which could contribute to the early stages of neurodegenerative diseases.
Led by Martina Hallegger, Anob Chakrabarti and Flora Lee, and with fantastic collaborators from Jim Shorter's lab and our Ljubljana satellite, as well as Nick Fawzi, Rickie Patani and Nick Luscombe. More from Martina on Twitter.
A free CLIP analysis pipeline and web platform
With Luscombe lab and collaborators, we co-developed a Nextflow analysis pipeline and a web server iMaps for streamlined analysis of CLIP data, which is freely available for general use. Read more about it here.
iMaps can be used to obtain public CLIP data, to analyse unpublished data in a secure manner, and to share your data publicly upon publication. Read more about its documentation and tutorial. A new iMaps site is in preparation, which will be fully based on the Nextflow pipeline and both its front- and back-end will be open access. It will contain many new and interactive functionalities, and will become fully operational in September (at that point, data will also be seamlessly transferred from old to new iMaps). Current iMaps can be used till then, and public data is available at both sites.
Recently published methods
iiCLIP: An improved iCLIP protocol that is technically convenient and efficient, enables quality control via non-radioactive analysis of protein-RNA complexes, and produces data of high specificity.
Ultraplex: Software for user friendly, streamlined and robust demultiplexing of complex sequencing libraries, such as those produced by various CLIP and ribosome profiling protocols.
clipplotr: A command-line tool for visual comparative and integrative analyses with normalisation and smoothing options for data to be shown alongside reference annotation tracks and functional genomic data.
Ribocutter: A streamlined Cas9-based protocol for removing abundant rRNA/ncRNA contaminants from Ribo-seq, CLIP or other small RNA-seq libraries and a software tool for designing ready-to-order sgRNA templates.
PEKA: Positionally-enriched k-mer analysis, a computational tool for analysis of enriched motifs from CLIP datasets, which minimises the impact of technical and regional genomic biases by internal data normalisation.
13C-dynamods: A 13C labeling approach to quantify the turnover of base modifications in newly transcribed RNA, which enables studies of the origin of modified RNAs and its dynamics under nonstationary conditions.
SPACE: Silica Particle Assisted Chromatin Enrichment to isolate global and regional chromatin components with high specificity and sensitivity, and SPACEmap to identify the chromatin-contact regions in proteins.
On the move!
On 1/4/22, the team moved from UCL to the KCL, where Jernej took the position of UK DRI Centre Director at KCL. The lab will gradually transition from its current secondment at the Francis Crick institute.