I mentioned BCL11A in a previous blog (More on Haemoglobin F – 16/04/14). It is a protein molecule which is critically important for switching off the production of haemoglobin F (Hb F) after birth and for maintaining low levels of Hb F throughout adult life. A series of scientific papers from a team at The Children’s Hospital and the Dana Farber Cancer Institute in Boston, led by Professor Stuart Orkin, has clarified the role of this protein in the switch from Hb F to Hb A synthesis, and opened up the way for the development of new treatments for sickle cell disease.
The protein molecule BCL11A, coded for by a gene on chromosome 2, suppresses the synthesis of Hb F. The presence of BCL11A is essential both for the switch from Hb F to Hb A production in early life and for the continuing suppression of Hb F synthesis thereafter. Most importantly, in transgenic mice with sickle cell disease, “knockout” of the BCL11A gene is sufficient, on it’s own, to prevent the complications of sickle cell disease, by stimulating high level Hb F production.
How does BCL11A work? Needless to say this seems to be very complex. It would appear that BCL11A associates with a series of other proteins, which it assembles into a “repressor complex”. This repressor complex then binds, via the action of BCL11A, to three specific areas in the globin gene complex, where the haemoglobin genes are found. The repressor complex seems to induce a change in the architecture of the haemoglobin genes, such that looping of part of chromosome 11 containing the haemoglobin genes, brings the genes for Hb A into close proximity with the Locus Control Region (LCR), which is the main activator of haemoglobin gene activity, excluding the genes for Hb F, and thereby stimulating the production of Hb A.
Because of it’s vital importance in controlling whether Hb A or Hb F is made, BCL11A would therefore seem to be an ideal molecular target for potential drugs to treat sickle cell disease; inactivating BCL11A would stimulate Hb F synthesis, which in turn would have a beneficial effect on the symptoms and complications of sickle cell disease. As noted above, “knockout” of the BCL11A gene in transgenic mice with sickle cell disease was sufficient alone to transform the course of the disease in the affected animals. Unfortunately, the BCL11A protein is also found in other tissues, particularly the brain and immune system, where its function seems to be essential for life; mice who had both BCL11A genes deleted died in early infancy. Any new treatment would therefore have to specifically act on BCL11A in red cell precursors only, but until recently it was not clear how this could be achieved.
The big step forward came in a paper published in October last year. The group from Boston discovered that there is a specific region of DNA, which acts as an essential enhancer of the activity of the BCL11A gene, but only in red cell precursors. In other words, this newly discovered BCL11A enhancer is essential for modifying the activity of haemoglobin genes, but is not necessary at all for the actions of BCL11A in other tissues, such as the immune system.
This remarkable discovery opens the way for the development of drugs, which will work in red cell precursors only, via the BCL11A enhancer, to inhibit BCL11A production and thereby promote Hb F synthesis, whilst leaving BCL11A in other tissues completely unaffected.
Transcriptional silencing of gamma-globin by BCL11A involves long range interactions and co-operation with SOX6. Genes and Development 2010; volume 24, pages 783-798.
An erythroid enhancer of BCL11A subject to genetic variation determines foetal haemoglobin level. Science 2013; volume 342, pages 253-257.