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Function and dynamics of Lmo4-containing complexes during erythropoiesis

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Molecular secrets of red blood cells

European scientists are investigating the most basic molecular nuts and bolts of red blood cell manufacture. Therapies for blood disorders such as anaemia could be revolutionised as a result.

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Red blood cells (RBCs) carry oxygen to energy-hungry cells in the body. One effect of RBC shortage or malfunction is anaemia, which leaves the sufferer weak, short of energy and can lead to cardiovascular problems. For children, anaemia can mean problems with neurological function, learning difficulties and behavioural disturbances. To get to the bottom of disorders of RBC development, the EU-funded project Lmofundyn investigated the complex process whereby humans manage to make almost 2.5 million new RBCs per second. They focused on the transcription factor (TF) network. These are special proteins that lock onto the DNA to control the first stage of production of an RBC protein. Researchers focused on an important family of genes and their proteins, the LMOs. The role of LMO2 is well known in RBC formation but one of its partners, LMO4 has so far remained a mystery. To unravel the pathways that LMO4 plays a part in, Lmofundyn employed genetic manipulation using both standard laboratory techniques and other more ground-breaking methods. One technique is to tag a gene and then look for its coded protein which will also carry the tag. Using mass spectrometry to identify the tagged products, the project researchers found no less than 52 molecular partners for LMO4. To code for a protein, the LMO4 gene has uniquely shaped areas that lock onto other partner molecules. The project scientists used a newly developed method – chromatin immunoprecipitation sequencing (ChIP-Seq) – to locate these. The scientists used this technique to precisely map global binding sites for any protein of interest. Another approach used was to engineer knock-downs, where genes are disabled and are therefore incapable of producing their proteins. The expression of the gene is prevented and the protein level will be lowered at best or absent altogether.As well as the identification of new biochemical partners for LMO4, the scientists made a further breakthrough. They have for the first time gathered together evidence of a new role for the protein. It has been discovered that the protein can act as a gene repressor under certain circumstances during RBC manufacture. The complexity of the web of pathways in the production of red blood cells is mind-blowing. The Lmofundyn project has made significant headway to elucidating some of these. The work will form part of the ongoing modelling of RBC protein transcription factor (TF) networks.

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