By Michael McDevitt, MD, PhD

2008-12-06

Understanding the molecular basis for hemoglobin switching remains a Holy Grail of hematologists. Understanding how the human γ-globin gene is regulated has important clinical implications because increased levels of fetal hemoglobin (HbF) are beneficial to patients with sickle cell disease and β-thalassemia. Being able to more predictably, effectively, and safely turn on the γ-globin gene would be of great practical consequence.

It is only appropriate that here in San Francisco, where some of the very early diagnostic testing for the sickle cell allele was developed by Dr. Y. W. Kan and colleagues, ASH has assembled an exciting program that provides an update of current concepts and new approaches to hemoglobin gene regulation. During today's scientific committee session at 7:30 a.m. in Room 120-125 – North (repeated tomorrow at the same time and place), epigenetic control of globin gene expression will be presented. Dr. Douglas Higgs, of the MRC Molecular Haematology Unit, will lead off the presentations with a talk titled “Switching Genes On and Off During Hematopoiesis.” The Higgs laboratory has performed novel, highly ambitious large-scale investigations of the human and mouse alpha and beta globin loci for a number of years and has made numerous discoveries related to how transcriptional and epigenetic programs influence chromatin conformation and globin gene expression. Using a variety of technical approaches, Dr. Higgs will provide insights into temporal aspects of silencing factors, activating transcription factors, and epigenetic modifications in the alpha globin cluster. Fascinating descriptions of how chromosomal conformation and nuclear sub-localization change during hematopoiesis together with other observations will provide for us some of the general principles by which genes within their natural chromosomal environment are switched on and off during hematopoiesis.

In the second presentation of the session, Dr. Emery Bresnick, from the University of Wisconsin, will present “GATA Factor Mechanisms and Globin Gene Regulation.” The GATA factor family of transcription factors are critical for multiple key steps in hematopoiesis and regulate the expression of many important hematopoietic genes including those encoding the hemoglobin subunits. Dr. Bresnick will provide molecular, genetic, and epigenetic insights into the multi-step mechanisms underlying the control of γ-globin transcription. In particular, a focus on GATA-1-containing complexes, insights into how in vivo tissue-specific binding sites are identified, and chromatin remodeler complexes will provide new insights into the relationship between, and importance of, individual steps in the multi-step γ-globin activation mechanism.

In the final presentation of the session, Dr. Donald Lavelle, of the University of Illinois at Chicago, will investigate the role of DNA methylation in the developmental silencing of the γ-globin gene. The ability of pharmacological inhibitors of DNA methyltransferase (5-azacytidine; decitabine) to reactivate high-level expression of the γ-globin gene in experimental primates has led to clinical trials demonstrating that decitabine increased HbF to therapeutic levels in patients with sickle cell disease. The mechanism of action of the drug has not been definitively established, however. Experimental support for the hypothesis that γ-globin expression in adults is repressed by the binding of methyl DNA binding proteins with subsequent recruitment of co-repressor complexes will be reviewed.

Their observations that high level γ-globin expression in baboon erythroid progenitor cell cultures without a reduction of γ-globin gene DNA methylation suggests the existence of alternative mechanisms of activation as well. Potential p38 MAP kinase pathway and cell cycle regulatory pathways will be discussed. Dr. Lavelle’s presentation will emphasize that an increased understanding of upstream genetic, epigenetic, and signaling pathways that regulate the γ-globin gene regulation are likely to impact the design of future therapies to increase HbF levels.

Dr. McDevitt indicated no relevant conflicts of interest.

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