Multiprotein complexes in gene repression

Funded Activity Summary

DNA-binding proteins regulate gene expression to co-ordinate our development and physiology. These proteins operate by recognizing specific control sequences in target genes and turning these genes on or off. It may be possible to artificially regulate specific genes to treat certain inherited disorders. One of the most common genetic diseases worldwide is inherited haemoglobinopathy. Mutations in the adult beta haemoglobin gene cause diseases such as sickle cell anaemia and beta thalassaemia. These diseases can be seriously debilitating or lethal and often require lifelong treatment. Current treatments (such as repeated blood transfusion and subsequent iron chelation therapy) are demanding on the patient, expensive, and in the long run can be inneffective. Proposed future treatments involve reactivating normally silent haemoglobin genes (such as foetal haemoglobin) to compensate for the absence of adult beta haemoglobin. We have been studying a DNA-binding protein termed BKLF. We have shown that BKLF turns genes off and in particular we have shown using mammalian model systems that BKLF turns off the foetal haemoglobin gene. Inhibiting BKLF action therefore becomes an important goal, as this might lead to a reactivation of foetal haemoglobin to alleviate sickle cell anaemia and beta thalassaemia. We are seeking to understand the molecular mechanisms by which BKLF silences gene expression, to identify other proteins with which it operates, and to define their activities, in an effort to identify the best ways of inhibiting BKLF's action. Ultimately, studies on defined model genes such as the haemoglobin genes should elucidate general principles of gene regulation that may be useful in controlling gene expression in additional therapeutic or experimental contexts.

Funded Activity Details

Start Date: 01-01-2003

End Date: 01-01-2005

Funding Scheme: NHMRC Project Grants

Funding Amount: $455,250.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Oral and maxillofacial surgery

ANZSRC Socio-Economic Objective (SEO)

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Other Keywords

anaemia | blood | haematology | protein characterisation | thalassaemia | transcription factor | transcriptional regulation | zinc finger proteins

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