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RNA EDITING IN HEALTH AND DISEASE

Objective

"RNA editing is a type of programmed RNA sequence alteration that can result in a range of proteomic changes, from subtle fluctuations in output, to specific alterations in protein content. Editing is catalyzed by two classes of deaminases: those which convert adenosine to inosine (ADARs) and those which convert cytosine to uracil (APOBEC1). We have previously shown that APOBEC1-catalyzed editing in the transcriptome of macrophages leads to the generation of populations that are heterogeneous, and functionally diverse, enabling rapid population adaptation to different environmental settings.

Our first aim for this proposal is to extend our studies to additional immune cell subsets, focusing on cells that are recently recognized as ""plastic"" to define the contribution of editing to this plasticity of fate and function.

RNA editing of the type we study has also been demonstrated to be crucial for cancer progression. For instance, APOBEC1-deficiency significantly reduces tumour burden on cells of the intestine and colon that are prone to adenocarcinomas in the context of the APC-min mutation. This is also the case for testicular carcinomas in mouse models of such tumours. Thus, there is genetic evidence for a requirement for APOBEC1 and RNA editing to drive tumour progression, in two tumour contexts. Based on these data and on our recently deciphered role for APOBEC1 as a ""stealthy"" diversifier of cellular transcriptomes (and proteomic outcomes), we hypothesize that APOBEC1 drives tumour progression by editing select transcripts in tumour cells (or tumour stem cells), thus enabling the rapid adaptation of the tumour to the onslaught of the immune response.

Our second aim is to characterize the subset of edited transcripts in these model tumours (either at the population or at the single cell level) and understand their role to tumour survival and progression, both in mouse models of disease, and in human tumour samples (in collaboration with QP Hammarstrom, KI)."

Field of science

  • /medical and health sciences/medical biotechnology/cells technologies/stem cells
  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /medical and health sciences/clinical medicine/oncology/cancer

Call for proposal

ERC-2014-CoG
See other projects for this call

Funding Scheme

ERC-COG - Consolidator Grant

Host institution

DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Address
Im Neuenheimer Feld 280
69120 Heidelberg
Germany
Activity type
Research Organisations
EU contribution
€ 1 839 172,50

Beneficiaries (3)

DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Germany
EU contribution
€ 1 839 172,50
Address
Im Neuenheimer Feld 280
69120 Heidelberg
Activity type
Research Organisations
KAROLINSKA INSTITUTET
Sweden
EU contribution
€ 430 827,50
Address
Nobels Vag 5
17177 Stockholm
Activity type
Higher or Secondary Education Establishments
THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE

Participation ended

United Kingdom
EU contribution
€ 0
Address
Trinity Lane The Old Schools
CB2 1TN Cambridge
Activity type
Higher or Secondary Education Establishments