Objective
- To identifiy KOX zinc finger specific target sites and genes.
- To analyse human zinc finger gene clusters on chromosome 10 p11.1-q11.1.
- To map zinc finger genes to chromosomal loci.
- To determine the structure of the KRAB domain and characterize proteins mediating KRAB specific repressor functions.
- To generate knock-out mice with deleted zinc finger genes.
- To evaluate the potential of transcription response modifiers in HIV infections.
The identification and dissection of regulatory networks, which control the expression of human genes in space and time, would represent a breakthrough in both human genetics and developmental biology. Transcription factors of the Kruppel zinc finger type (ZNF) are nucleic acid binding factors which, due to the binding properties and organisation features of their finger domains, are each likely to bind to a small number of specific DNA sequences within the human genome. Furthermore, approximately one third of the 300 to 700 human ZNF genes contain a highly conserved protein domain (the KRAB domain), which is the strongest known repressor of transcription in any mammalian organism. The number, structure, biological activity and sequence conservation of ZNF genes studied in Xenopus and Drosophila indicates that they play a critical role in the control of gene expression. An important advance in our understanding of coordinated gene regulation will, therefore, be defining the precise function of specific KRAB zinc finger proteins in mammals and, in particular, in man. Significantly, once the function of one KRAB zinc finger protein has been conclusively determined, putative functions for other members of this huge family of transcriptional regulators can be assigned and investigated. In addition, this will enable the repression activity and binding specificity of these proteins to be considered for potential therapeutic use.
The aim of this proposal is to take a coordinated approach to the analysis of KRAB zinc finger genes and their products. This involves integrating the efforts of seven industrial and research laboratories in 5 EC member countries to resolve key issues concerning KRAB ZNF gene structure and function.
Specifically, the proposal has the following research aims:
1) Target sites and genes recognised by KRAB ZNF proteins will be isolated by both in vivo and in vitro methodologies;
(2) Proteins completing with the KRAB domain to effect repression in vivo will be cloned and characterised;
(3) The structure of both wild type and mutant KRAB domains and subdomains will be analysed by NMR;
(4) Novel zinc finger genes will be assigned to chromosomal loci and their relationship to known ZNF gene clusters investigated;
(5) The genomic structure, sequence, coordinate expression and phylogeny within and between individual ZNF gene clusters will be analysed;
(6) The biological functions of specific KRAB-ZNF proteins will be determined in rodent knockout models;
(7) Autoregulation of ZNF gene expression will be examined;
(8) Functions of proteins interacting with the KRAB domain will be analysed;
(9) The potential use of KRAB repressor domains in inhibiting HIV replication will be examined. (10) A model of KRAB specific gene function, utilizing results from 1-9together with data from the public domain, will be formulated.
Collectively, the above research aims will provide technical and conceptual advances in our understanding of zinc finger gene functions in particular and eukaryotic gene regulation in general. Furthermore, the outcome of this research initiative will enable the possibility that zinc finger domains can be used to direct effect or domains to specific sites in the genome to be explored. The potential for developing novel approaches to artificially control endogenous gene expression will, in turn, give a strong impetus to biotechnological enterprises within the EC. 01
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences chemical sciences inorganic chemistry transition metals
- natural sciences biological sciences biochemistry biomolecules proteins
- medical and health sciences health sciences infectious diseases RNA viruses HIV
- natural sciences mathematics pure mathematics mathematical analysis functional analysis
- medical and health sciences basic medicine medical genetics
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Coordinator
18055 Rostock
Germany
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