Rohrig, AE; (2013) Role for tumour suppressor Merlin in gene expression. Doctoral thesis , UCL (University College London).

Abstract

The tumour suppressor Merlin is mutated in the familial cancer syndrome Neurofibromatosis Type 2 (NF2) and in various sporadic tumours. Several lines of evidence show a role for Merlin in mediating contact-dependent inhibition of proliferation. Contact inhibition is essential for normal tissue homeostasis and its deregulation is a hallmark of cancer. Despite extensive efforts the mechanism underlying tumour suppression by Merlin remains elusive. A proteomics approach led to the identification of novel Merlin interacting proteins several of which are involved in gene expression, in particular transcription elongation, RNA processing and histone modifications, and are also deregulated in cancer. Among those are the RNA PolymeraseII-associated factor1 complex (Paf1C), CHD1, TAT-SF1 and spliceosome components. These interactions have been validated and mapped to Merlin’s FERM domain and loss-of-function Merlin mutations found in tumours invariably disrupt these interactions. The interaction of Merlin with the Paf1C is modulated by cell density and is required for Merlin’s tumour suppressor function. We find a remarkable case of tumour suppressor gene hypersensitivity in Merlin-deficient cells that correlates with Merlin’s ability to regulate gene expression. Using genome-wide expression profiling we identify a gene signature associated with growth arrest by Merlin expression that is consistent with Merlin’s role in mediating contact inhibition and suggests a role for Merlin in innate immunity and communication with the microenvironment. By integrating re-expression and knockdown gene signatures a core Merlin signature has been defined that correlates with NF2 mutational status and suggests differential drug sensitivities and potential therapeutic targets for treatment of NF2-related tumours. Using genome-wide occupancy analysis we identify a subset of genes where Merlin expression regulates association of the Paf1C with chromatin of coding regions. Some of these regulated genes are known target genes of YAP, the transcriptional co-activator of the Hippo tumour suppressor pathway. Although YAP expression rescues growth arrest by Merlin, Merlin can regulate expression independently of YAP. A model is proposed where Merlin functions parallel to YAP to regulate gene expression at the elongation level through the Paf1C.

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