Title: The Complex Life of RNA or how to Modify the Cancer Transcriptome; new mechanisms and therapeutic opportunities
Funder: Cancer Research UK

Abstract: We will harness the rapidly evolving world of RNA biology to improve our understanding of cancer etiology and to generate novel strategies for anti-cancer therapeutics and diagnostics. BACKGROUND RNA integrates information from the genome and the environment to shape the fate of cells, tissues, organs and organisms. Deregulation of cellular RNA, non- coding and coding, is a major driver of tumour formation and cancer progression. Furthermore, profiling of tumour RNA has proven effective in stratifying human cancer. While much is known about the regulation of RNA transcription through DNA-binding transcription factors, chromatin modifiers and epigenetics, the co- and post-transcriptional regulation or RNA is much less understood. In addition, tRNA and rRNA which directly regulate the protein output of the genome have recently emerged as important steps of control. AIMS We have identified three key steps in the life of cellular RNA that might act as new starting points for anti-canccer therapeutics: the co-transcriptional sorting of nascent RNA, the regulation of RNA turnover through 3' uridylation and the regulatory role of cytosine methylation in RNA. Our specific aims are: Aim 1: Nuclear RNA helicases in cancer: AQUARIUS/EMB-4 and SNRP200/BBR2/SNRP-200 Aim 2: Terminal nucleotidyl transferases and their RNA targets in cancer Aim 3: How does 5-methyl-cytosine RNA metabolism drive gene expression in stress and cancer? METHODS To deliver this project we will take advantage of a combination of technologies including C. elegans genetics, human cancer cell culture, genome editing, molecular biology and RNA biochemistry, chemical probing, high-throughput sequencing and cell biology. All of these approaches will generate complex data sets that will be analysed using advanced computational tools that we have implemented or are developing within the group. OUTCOMES RNA is the key molecule that cells use to interpret the genome. The biology and pathology of co- and post-transcriptional RNA modification is largely unknown. In analogy to epigenetics this emerging field is sometimes referred to as RNA epigenetics. Emerging data suggests that RNA epigenetics will have as a profound impact on cancer biology as epigenetics has had. RNA epigenetics has the potential to open up RNA as a largely unexplored target in anti-cancer therapy. We expect that this work will significantly impact our fundamental understanding of the role of RNA epigenetics in cancer. In addition, we expect to identify new therapeutic starting points that might be developed into combination therapies, e.g. when paired with immunotherapy.

Lay abstract: We will harness the rapidly evolving world of RNA biology to improve our understanding of cancer etiology and to generate novel strategies for anti-cancer therapeutics and diagnostics. BACKGROUND RNA integrates information from the genome and the environment to shape the fate of cells, tissues, organs and organisms. Deregulation of cellular RNA, non- coding and coding, is a major driver of tumour formation and cancer progression. Furthermore, profiling of tumour RNA has proven effective in stratifying human cancer. While much is known about the regulation of RNA transcription through DNA-binding transcription factors, chromatin modifiers and epigenetics, the co- and post-transcriptional regulation or RNA is much less understood. In addition, tRNA and rRNA which directly regulate the protein output of the genome have recently emerged as important steps of control. AIMS We have identified three key steps in the life of cellular RNA that might act as new starting points for anti-canccer therapeutics: the co-transcriptional sorting of nascent RNA, the regulation of RNA turnover through 3' uridylation and the regulatory role of cytosine methylation in RNA. Our specific aims are: Aim 1: Nuclear RNA helicases in cancer: AQUARIUS/EMB-4 and SNRP200/BBR2/SNRP-200 Aim 2: Terminal nucleotidyl transferases and their RNA targets in cancer Aim 3: How does 5-methyl-cytosine RNA metabolism drive gene expression in stress and cancer? METHODS To deliver this project we will take advantage of a combination of technologies including C. elegans genetics, human cancer cell culture, genome editing, molecular biology and RNA biochemistry, chemical probing, high-throughput sequencing and cell biology. All of these approaches will generate complex data sets that will be analysed using advanced computational tools that we have implemented or are developing within the group. OUTCOMES RNA is the key molecule that cells use to interpret the genome. The biology and pathology of co- and post-transcriptional RNA modification is largely unknown. In analogy to epigenetics this emerging field is sometimes referred to as RNA epigenetics. Emerging data suggests that RNA epigenetics will have as a profound impact on cancer biology as epigenetics has had. RNA epigenetics has the potential to open up RNA as a largely unexplored target in anti-cancer therapy. We expect that this work will significantly impact our fundamental understanding of the role of RNA epigenetics in cancer. In addition, we expect to identify new therapeutic starting points that might be developed into combination therapies, e.g. when paired with immunotherapy.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE