About the Project
- To foster the integration of elite European research teams from experimental and computational research communities to create a unique world-leading programme in the systems biology of inflammation.
- To acquire new knowledge and understanding of the transcriptional control of the inflammatory response.
- To employ complementary state-of-the-art technologies to quantitatively describe the minimal central event in transcriptional control of inflammation, namely TF binding to DNA.
- To develop new dedicated computational and functional genomic technologies to build and experimentally validate integrative models of transcriptional response in inflammation based on quantitative description of TF action.
- To implement training activities that will engage a new generation of the systems biology scientists.
- To provide accessible information and outreach for engaging the wider scientific community via open workshops, publications as well as the consortium web-site.
The key objective of the Modelling Inflammation (Model-In) consortium is to provide mechanism-based mathematical models linking genomic determinants to transcriptional control of a basic biological process, namely the inflammatory response. Model-In brings together elite European research teams to create a world-leading programme and to set up new standards for quantitative studies of key immunological processes by employing state-of-the-art multidisciplinary fundamental genomics, computational and molecular biology approaches and by developing novel dedicated technologies.
Inflammation as a transcriptional response
Inflammation is a normal and self-limiting physiological response to infection and injury but can lead to extensive tissue damage and disability when elicited in excess or in a sustained manner. Pathological consequences of chronic inflammatory responses include a variety of diseases with huge social impact ranging from autoimmune diseases (such as rheumatoid arthritis (RA), Crohn’s disease, ankylosing spondylitis and multiple sclerosis) to septic shock and cancer. The pathogenesis of chronic autoimmune diseases and cancer is often associated with sustained production of normally transiently expressed inflammatory cytokines (e.g. TNF, IL-1, IL-6, IL-8 etc)(1).
Although the design and the development of anti-inflammatory drugs is continuously evolving, there is a need for selective drugs targeting basic mechanisms underlying the inflammatory response, ideally without having a deleterious effect on innate immunity, which is an essential first line of defense against microbes conserved from flies to humans. Inflammatory responses are first initiated and then maintained by transcription of genes whose products recruit and activate leukocytes, increase vascular permeability, amplify the response, and protect inflammatory and tissue cells from apoptosis. Regulation of transcription and gene expression for many inflammatory cytokines involves combinations of transcription factors (TFs) including those of the NF-κB, IRF and AP-1 families (2). The activity of a given transcription factor is determined by its binding to a specific promoter site and subsequent transactivation. Therefore, basic events at the hearth of every inflammatory response, either self-resolving or excessive and sustained, occur in cell nuclei and are underpinned by the dynamic relationships between genomic cis-regulatory (DNA sequence) determinants and trans-acting factors interacting with them.
TF-DNA interaction affinity as a determinant of transcriptional specificity
The first step towards a mechanistic understanding of inflammatory gene control is the accurate and quantitative annotation of the specific interactions between TFs and their cognate binding sites (TFBS). A given TF typically recognizes a specific but often relatively degenerate sequence pattern called a binding motif, which is usually 6-20 base pairs in length. In the motif, some nucleotides tend to occur more often than others in specific positions. Different TFs prefer different binding motifs, and multiple TFs can bind cooperatively to a cis-element that contains several different TFBSs clustered together. At any time, the particular composition of transcription factors active in the cell nucleus determines which subset of cis-elements is bound and which genes are activated. The cis-regulatory elements are thus the hardwired “control logic” in the genome (3). Although most genes in the human genome have been identified and annotated, the location, properties and physiological behaviour of cis-elements that control their expression are largely unknown. The identification and characterization of such elements and the ability to model their function is a key challenge of genomic biology, whose solution will allow understanding how a specific genomic organization translates into regulated responses. Tackling this challenge requires the acquisition of new types of quantitative experimental data as well as the development of ad-hoc computational and functional genomic approaches.
Model study: Inflammatory transcription factors
During the course of this project we will focus on the selected families of inflammatory transcription factors (NF-κB, IRFs and AP-1 proteins) and will employ the unique combination of skills, state-of-the-art and newly developed technologies brought together by this consortium to examine the link between the sequence of individual TFBS and tightly controlled expression of inflammatory genes. The key regulator of gene expression in inflammation is the family of transcription factors NF-κB/Rel (4). Ways to modulate levels of these transcription factors in inflammation and cancer are considered to be of potential therapeutic importance (5,6). Many of the NF-κB dependent immune genes are also coregulated by other families of transcription factors, including AP-1/CREB (activating protein 1 and cAMP responsive element binding protein) and IRF (interferon regulatory factor), which work in conjunction with each other at different cis-regulatory regions.
In conclusion, Model-In proposes to quantitatively study the transcriptional basis of one of the major fundamental biological processes, namely the inflammatory response. To address the goal of the HEALTH-2007-2.1.2-5 call, we chose a TFBS-centred approach to understanding and quantitatively describing the transcriptional control of the inflammatory response, consisting of the rational combination of quantitative in vitro and in vivo analyses, mathematical modelling and in vivo perturbation experiments.
The unique combination of skills and state-of-the-art developed technologies brought together by this consortium will allow us to tackle this question with the level of accuracy and physiological relevance not achievable with individual efforts. This proposal aims to set up new standards for studies in systems biology and create a framework for quantitative description of this key immunological process.
Model-In will also engage widely with European systems biology research community. It will organise annual workshops in different parts of Europe (including open workshop in a new EU member state Bulgaria) and will provide training for a new generation of European scientists in systems biology as well as foster interactions, exchange and synergy among the principal laboratories in the field of mammalian transcription. In addition, Model-In will develop a range of web-resources via which it will disseminate the results obtained within the project, provide the information on the generated standards, protocols and tools, as well as the educational material for the wider community.