MNRGN

The elucidation of the nuclear receptor gene regulatory network in mouse microglia

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 Obiettivo del progetto (Objective)

'Nuclear receptors (NR) constitute a large transcription factor (TF) family with ~50 NRs identified in human or mouse. NRs have crucial roles in multiple tissues and biological processes. Consequently, misregulation of NR gene expression has been linked to several severe pathologies including cancer and neurodegenerative diseases. Despite their pathological importance, the core NR gene regulatory network (i.e. the protein-DNA interactions or PDIs controlling the expression of NR genes) has been very poorly studied. We will initiate the elucidation of the NR gene regulatory network by focusing on primary microglial cells as a non-transformed, and homogeneous model system. Microglia are poorly characterized macrophage-like brain immune cells, which may have both neurotoxic and neuroprotective properties. The majority of NRs exhibit a very dynamic expression profile in activated macrophages. Together with our preliminary data, this suggests that NRs may play a central role in microglial gene regulatory networks as well. The biological question of this proposal is to understand “which, when, and how NRs are expressed in microglia in response to neurotoxic stimuli”. We will (1) identify the temporal gene expression profiles of NRs in activated microglia; (2) identify the TFs controlling differentially expressed microglial NRs by uniquely combining two novel technologies (chromosome conformation capture and high-throughput PDI screening), whose respective co-inventors will both be involved in the project; and (3) experimentally validate the detected PDIs in microglia using siRNA and ChIP. The resulting list of high-confidence PDIs will be used to generate a first microglial NR gene regulatory network. The latter can be used for future modeling efforts to predict how the network will behave under distinct physiological conditions, or how to manipulate the network such that the neuroprotective properties of microglia are stimulated and its neurotoxic properties suppressed.'

Introduzione (Teaser)

Unravelling the causes of diseases like cancer and dementia require knowledge at the atomic level in a cell. An EU-funded project is making headway in this field through a study of nuclear receptors, key molecules in cell maintenance and development.

Descrizione progetto (Article)

The activation of genes so that they can make proteins is a very intricate process - a gene must be switched on at the right time in relation to other processes in a cell. One small slip and genetic and biochemical anarchy takes over, usually made obvious by the onset of disease.

An EU-funded project MNRGN chose to study a certain type of white blood cell found in the brain, microglia and the way they manufacture proteins. These cells are thought to play a big part in degenerative diseases like Alzheimer's and Parkinson's as well as normal ageing. Releasing toxins, they can create a state of chaos and prevent normal message transmission in the brain.

Within all cells including microglia, nuclear receptors (NRs) can sense the presence of certain hormones and other molecules. As such, they are responsible for the regulation of certain genes concerned with development, internal balance and metabolism of a cell and therefore the whole organism.

Two state-of-the-art technologies were used to sort out exactly how the DNA, in conjunction with the NRs, works in these cells. Chromosome conformation capture is used to analyse the organisation of a chromosome as the cell goes about its day to day operations. High-throughput protein-DNA interaction screening helps to match genes with the proteins they code for.

So far, the results of the project are very encouraging. The position and function of many genes under study have been precisely outlined. A little disappointing is that the culture system for the microglia has not been consistent. For future study, the MNGRN scientists aim to change their focus to fat cell development.

The growth of a fully mature fat cell will still allow analysis of cascades of interlinked gene pathways and all the members of DNA and RNA involved in the production of proteins. As genes, their function and malfunction, are the basis of diseases like cancer and deterioration, including ageing, the outcome of this research may be very important indeed.