Biology subjects

Emmett, W.

Publications and source records attributed to Emmett, W..

3 recordsLinked to original sources

bioRxiv2019

Role for Merlin/NF2 in transcription elongation through interaction with the PAF complex

The PAF complex (PAFC) coordinates transcription elongation and mRNA processing events and its CDC73/parafibromin subunit functions as a tumour suppressor. The NF2/Merlin tumour suppressor functions at the cell cortex and nucleus and is a key mediator of contact inhibition. Here we provide a direct link between nuclear Merlin and transcription elongation controlled by cell-cell adhesion. Merlin interacts with the PAFC in a cell density-dependent manner and tumour-derived inactivating mutations in both Merlin and CDC73 mutually disrupt their interaction. Growth suppression by Merlin requires CDC73 and Merlin regulates PAFC association with chromatin in a subset of genes. We also identify by CDC73 affinity-proteomics a role for FAT cadherins in regulating the Merlin-PAFC interaction. Our results suggest that in addition to its function within the Hippo pathway, nuclear Merlin is part of a tumour suppressor network which coordinates postinitiation steps of the transcription cycle of genes mediating in contact inhibition.

cancer biology↗

bioRxiv2018

Heteromeric RNP assembly at LINEs controls lineage-specific RNA processing

It is challenging for RNA processing machineries to select exons within long intronic regions. We find that intronic LINE repeat sequences (LINEs) contribute to this selection by recruiting dozens of RNA-binding proteins (RBPs). This includes MATR3, which promotes binding of PTBP1 to multivalent binding sites in LINEs. Both RBPs repress splicing and 3 end processing within and around LINEs, as demonstrated in cultured human cells and mouse brain. Notably, repressive RBPs preferentially bind to evolutionarily young LINEs, which are confined to deep intronic regions. These RBPs insulate both LINEs and surrounding regions from RNA processing. Upon evolutionary divergence, gradual loss of insulation diversifies the roles of LINEs. Older LINEs are located closer to exons, are a common source of tissue-specific exons, and increasingly bind to RBPs that enhance RNA processing. Thus, LINEs are hubs for assembly of repressive RBPs, and contribute to evolution of new, lineage-specific transcripts in mammals.

genomics↗

bioRxiv2017

Association study of schizophrenia with variants in miR-137 binding sites

There is strong cumulative evidence for the involvement of miR-137 and its targets in the aetiology of schizophrenia. Here we test whether variants, especially rare variants, in miR137 binding sites are associated with schizophrenia in an exome-sequenced sample of 4225 cases and 5834 controls. A weighted burden test using 372 variants was significant at p=0.024. The sample size is too small to implicate individual variants or genes but overall this finding provides further support for the hypothesis that disruption of miR-137 binding sites can increase the risk of schizophrenia, perhaps by leading to over-expression of the target gene. These findings could be followed up by genotyping these variants in larger samples and by experimentally testing whether they do indeed effect expression. When carrying out exome sequencing it is important to include UTRs so that disruption of microRNA bindings sites can be detected.

genetics↗