A new genomic resource may help researchers unravel the role of key RNA-binding proteins in ALS. The atlas, developed at the Riken Institute in Yokohama, Japan, contains 27,919 long non-coding RNAs – including 19,175 potentially functional RNAs in the human genome. Many of the genes encoding these RNAs are expressed in the central nervous system and overlap disease-linked single nucleotide polymorphisms (SNPs) including ALS, suggesting that these RNAs may play a role in these diseases. The resource, developed as part of the FANTOM5 initiative, is based on genome-wide 5’ cap analysis of human gene expression data sets known as CAGE. The compendium is the largest human long non-coding RNA atlas created to date.
Researchers first suspected that long non-coding RNAs may play a role in ALS by studying the function of TDP-43, a key RNA-binding protein that is aggregated in the cytoplasm of motor neurons in most forms of the disease. Reporting in 2011, a research team led by University of California’s Don Cleveland in San Diego found that the reduction of TDP-43 resulted in the dysregulation of 59 long non-coding RNAs– at least in the mouse (Polymenidou et al., 2011; see March 2011 news). The approach, which involved the injection of antisense oligonucleotides and subsequent RNAseq analysis, aimed to identify RNAs that were likely regulated by TDP-43 in the brain and spinal cord.
The results coincided with a study, led by MRC’s Jernej Ule in Cambridge, England, that found that 5% of RNAs in post mortem human brain tissue bound to TDP-43 were long non-coding RNAs (Tollervey et al., 2011; see March 2011 news). The approach, known as iCLIP analysis, enabled Ule’s team to identify RNAs that bound and therefore may be regulated by TDP-43.
Together, the results suggest that TDP-43 may regulate the processing and/or the stability of key long non-coding RNAs in motor neurons. And, the dysregulation of these RNAs may play a role in most forms of the disease.
The resource is published online on March 1 in Nature. The atlas of long non-coding RNAs can be accessed in a database on the FANTOM5 website located here.
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