NeuroUTR · Systematic investigation of the functional coupling between transcriptional and post-transcriptional regulatory interactions underlying tissue-specific 3'UTRs variability.

Systematic investigation of the functional coupling between transcriptional and post-transcriptional regulatory interactions underlying tissue-specific 3'UTRs variability.

The appropriate functioning of the different tissues that compose our body is enabled by the precise and coordinated expression of specific gene-sets at defined time-point in specific cell types. Disruption in gene expression regulation can lead to various and complex disorders such as neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and incurable motor neuron disease (MND) characterised by disruptions in gene metabolism and protein homeostasis. If a growing number of causative gene mutations are being identified in ALS, the aetiology is still unknown and the early molecular events underlying the disease remain poorly understood. As a dramatic consequence, no effective treatments have been developed for this devastating disease that involves paralysis and death within 3-5 years of diagnosis. In the last 10 years, major steps have been achieved in the development of technologies that enable the simultaneous analysis of all the genes that are expressed in a specific cell type, also called RNA-seq data, shedding light on various cellular mechanisms and disorders. Here we aimed to develop bioinformatics methods and mathematical models to RNA-seq data from neurons of various sources, including human ALS patients, in order to better understand the molecular mechanisms underlying neuronal development and diseases. In doing this, we have re-annotated the boundaries of genes and quantified their usage from RNA-seq data. Next we have applied and expanded existing methods to two distinct RNA-seq data-sets leading to the following key findings: in collaboration with the laboratory of Antonella Riccio (MRC Laboratory for Molecular Cell Biology at University College London) we have uncovered the mechanisms underlying the remodeling in the axons of the products of a gene, the transcripts. In collaboration with Rickie Patani (Francis Crick Institute) and Jernej Ule (Francis Crick Institute), we have identified the exact cascade of gene regulatory events underlying MN development and demonstrated an acceleration of this process in samples derived from ALS patients. In doing this project we have not only advanced our current knowledge about RNA regulation but we have enabled a better understanding of the regulatory mechanisms underlying ALS, opening in the long term, the future development of new therapies that ameliorate the regulation of genes in neurodegenerative diseases.

Data: CORDIS, © European Union