RNA methylation in normal and malignant blood development

  • Kats, Lev (Primary Chief Investigator (PCI))
  • Das, Partha (Chief Investigator (CI))

Project: Research

Project Details

Project Description

Studies of the ‘epigenome’ over the past 30 years have demonstrated that covalently linked modifications of DNA and histones are a major determinant of
gene expression. The epigenome is dynamically regulated during development and its dysregulation contributes to many disorders including cancer. As is the
case with DNA and histones, RNA can also be modified and to date more than 150 chemical groups that decorate all four canonical RNA nucleotides have
been described. While these modifications undoubtedly carry genetic information, their study has lagged far behind that of DNA and histone modifications
and their functional relevance remains largely unknown. Methylation of the N6 position of adenosine (m6A) is the most common alteration on eukaryotic
messenger RNA (mRNA). Recent studies have begun to identify writers, readers and erasers of this epitranscriptomic mark and have demonstrated that it has
broad physiological roles in RNA splicing, stability, decay and translation. As m6A does not affect Watson-Crick base pairing, specialised sequencing
methods are required to determine its precise localisation in the transcriptome. We have developed a high-sensitivity m6A-seq protocol and herein we propose
to comprehensively analyse the function of m6A in normal blood development and leukaemia. Specifically, we will: (1) profile the dynamics of m6A RNA
methylation across 14 stages of haematopoietic differentiation; (2) determine how m6A localisation is altered in leukaemic cells; (3) identify key
haematopoietic factors regulated by the m6A pathway; and (4) provide deep mechanistic insights into the m6A writer complex. We have already produced
significant preliminary data to validate our approach and given the experience of the CIs and AIs we are highly likely to be able to address our aims within the
proposed timeframe and budget. Therefore, this application represents an important and realistic opportunity to advance our understanding of human
physiology and disease
Effective start/end date1/01/2031/12/22