Nature volume 603, pages 131–137 ( 2022) Cite this articleĪmyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating adult-onset neurodegenerative disorders with shared genetic causes and common pathological aggregates 6. 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.TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A 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.ġ3C-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.
Tdp new london software#
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. Ultraplex : Software for user friendly, streamlined and robust demultiplexing of complex sequencing libraries, such as those produced by various CLIP and ribosome profiling protocols.Ĭlipplotr : 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. 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. Such selective deregulation might contribute to the early stages of neurodegenerative diseases that involve TDP-43. Condensation is also required for TDP-43 regulation of a subset of its target 3’UTR isoforms, including autoregulation of TDP-43 itself. We refer to such molecular-scale assemblies as ‘binding region condensates’.
Tdp new london full#
We exploited the full potential of comparative iCLIP to find that the condensation capacity of TDP-43 is required for efficient binding to long RNA regions with widely dispersed UG-rich motifs. 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. We created variants of TDP-43 with a gradient of condensation properties as evident by phase separation in vitro, foci formation and RNA binding and regulation in cells. We addressed the long-standing question of how TDP-43 condensation influences its RNA binding specificity. Hallegger et al, TDP-43 condensation properties specify its RNA-binding and regulatory repertoire Cell.
We hope our discoveries will open up opportunities to develop new RNA-based therapies. We investigate how faulty RNPs lead to conditions affecting the nervous system, particularly neurodegenerative diseases such as amyotrophic lateral sclerosis, and how changes in RNPs contributed to brain evolution. In particular, we want to understand how RNPs contribute to the function of nerve cells in development, or their degeneration in disease. To understand how these interactions contribute to cellular functions, we develop new techniques that reveal protein-RNA and RNA-RNA interactions within cells. These proteins guide the RNA on its journey through the cell, while the RNAs also regulate the functions of bound proteins. RNAs are coated by proteins to form ribonucleoprotein complexes (RNPs). We study how RNA networks regulate gene expression in cells. In ‘modern’ cells, RNA molecules carry genetic information from DNA to proteins, and in addition they form wonderfully intricate networks that fine-tune the workings of a cell. According to the RNA world hypothesis, these talents stem from the central role of RNA at the origin of life. RNA is a multitalented molecule: it can store genetic information as well as catalyse chemical reactions.
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