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The inflammatory gene expression program in macrophages: An integrative approach for the systematic characterization of transcriptional co-regulators

Objective

Tissue responses to microbial and endogenous danger signals involve the activation of both resident and monocyte-derived macrophages, as well as the coordinated inducible expression of hundreds of inflammatory genes. Gene transcription is controlled by the information contained in thousands of genomic regulatory elements (enhancers and promoters), which is first read by transcription factors (TFs) and then integrated and relayed to the transcriptional machinery via an array of co-regulators with disparate biochemical activities and functions. The recent work of several groups, including our own, has extensively characterized how in macrophages the genomic regulatory sequences controlling inflammatory gene expression are coordinately bound and activated by myeloid lineage-determining TFs and broadly expressed stimulus-activated TFs. However, we still have a very incomplete understanding of the necessary next step in the process, namely how distinct combinations of DNA-bound TFs regulate recruitment and function of the co-regulators and machineries that control gene transcription.
Here, I propose to systematically identify the complement of co-regulators that control the induction of inflammatory genes in macrophages, which will be then mechanistically and functionally characterized both in vitro and in vivo. By integrating cutting edge genomic and computational approaches with focused genetic screens and biochemical analyses, and eventually validating relevant results in mouse models, this project aims at obtaining an unprecedented level of understanding of the information flow linking genomic regulatory elements to inflammatory gene transcription.

Call for proposal

ERC-2015-AdG
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Funding Scheme

ERC-ADG - Advanced Grant

Host institution

ISTITUTO EUROPEO DI ONCOLOGIA SRL
Address
Via Filodrammatici 10
20121 Milano
Italy
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
EU contribution
€ 1 377 911,71

Beneficiaries (2)

ISTITUTO EUROPEO DI ONCOLOGIA SRL
Italy
EU contribution
€ 1 377 911,71
Address
Via Filodrammatici 10
20121 Milano
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
HUMANITAS UNIVERSITY

Participation ended

Italy
EU contribution
€ 1 122 088,29
Address
Via Rita Levi Montalcini Snc
20090 Pieve Emanuele
Activity type
Higher or Secondary Education Establishments