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Noncoding and Translational Modulation of Gene Expression and Epigenetic Changes

Objective

"Gene expression studies rely on high throughput techniques, which do not take in account conceptual limits. I will overcome this situation by exploiting two biological facts. First, RNAs that are important in tissue function are a subset of the global mass, but are always associated with the ribosomal machinery and as such should be identified. Second, gene expression is the outcome of dynamic fluctuations that with time create a unique expression pattern. We need to dynamically label cell populations that undergo stress and follow them to generate a gene expression signature. To achieve my goal, I will consider: 1. Translational stress generated by viral infection or accumulation of misfolded proteins; 2. human CD4+ T lymphocyte subsets which are key to orchestrate immune responses; 3. EIF6 model of metabolic reprogramming.
1. Activation of eIF2alpha phosphorylation by viral infection generates a translational response in which silent mRNAs containing upstream ORFs (uORF) are translated. I will exploit this observation to construct the first in vivo reporter model of translational stress. We will label genetically cells that have translational stress, to identify all the changes that a single cell undergoes after viral infection/accumulation of undegraded proteins.
2. I will selectively sequence for the first time mRNAs and ncRNAs associated with the ribosomal machinery in human cells with a defined functional status.
3. Spectacular data have shown that translation factor eIF6 regulates tumorigenesis by inducing a profound metabolic reprogramming. This observation suggests that, in vivo, translation acts upstream of transcription. We will model how a short translational input results in a complex epigenetic change.
Significance: a revolution in finding biomarkers/drug targets. Generate a map of predictors of the process from stress to disease. Dscriminate biologically active sequences from background. Define how transient translation reshapes gene expression."

Field of science

  • /natural sciences/biological sciences/genetics and heredity/rna
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins

Call for proposal

ERC-2013-ADG
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

UNIVERSITA DEGLI STUDI DI MILANO
Address
Via Festa Del Perdono 7
20122 Milano
Italy
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 737 588,74
Principal investigator
Stefano Biffo (Prof.)
Administrative Contact
Stefania Varotto (Ms.)

Beneficiaries (3)

UNIVERSITA DEGLI STUDI DI MILANO
Italy
EU contribution
€ 737 588,74
Address
Via Festa Del Perdono 7
20122 Milano
Activity type
Higher or Secondary Education Establishments
Principal investigator
Stefano Biffo (Prof.)
Administrative Contact
Stefania Varotto (Ms.)
FONDAZIONE ISTITUTO NAZIONALE DI GENETICA MOLECOLARE INGM
Italy
EU contribution
€ 1 716 160
Address
Via Francesco Sforza 35
20122 Milano
Activity type
Research Organisations
Administrative Contact
Stefano Apollonio (Mr.)
UNIVERSITA DEGLI STUDI DEL PIEMONTE ORIENTALE AMEDEO AVOGADRO

Participation ended

Italy
EU contribution
€ 42 251,26
Address
Duomo 6
13100 Vercelli
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Cristina Coloccini (Mrs.)