Transcription. Gene expression--where to start?

then the causative SNP either has a non–tissue-specific effect on transcription, or it acts at the posttranscriptional level, an issue that remains to be resolved. Although the results are consistent with the long isoforms of BCL11A functioning to suppress HbF production in a dose-dependent manner, they do not distinguish between a direct effect on γ-globin gene expression and an indirect effect on the kinetics of erythropoiesis that might cause cells containing HbF to be overproduced (9). Additional findings of Sankaran et al. argue strongly in favor of the former model. For example, BCL11A was found to interact with multiple components of the nucleosome remodeling and histone deacetylase (NuRD) complex, which functions in transcriptional repression (10), as well as with GATA-1 and FOG-1, the major activating transcription factor and cofactor, respectively, of the erythroid lineage (11). Further, RNA interference specific for BCL11A in primary erythroid progenitors increased γ-globin mRNA expression and HbF production without inducing a generalized effect on cellular differentiation or altering expression of known globin gene transcription factors. Finally, chromatin immunoprecipitation revealed that BCL11A binds to multiple regions within the human β-globin locus that control silencing of the γ-globin gene (7). Thus, BCL11A plays an important role in fetal-to-adult hemoglobin switching during normal erythropoiesis, and its expression in adult erythroid cells affects the amount of HbF produced. This raises questions about what controls the stage-specific shift between the long and short BCL11A isoforms, and the molecular mechanism by which BCL11A represses γ-globin gene expression. It is also not clear which genetic variant in BCL11A sets the expression level of this gene, nor how it functions in this capacity. Higherresolution studies of BCL11A chromatin occupancy, functional characterization of the putative cisregulatory elements containing these binding sites, and sequencing of the entire region of BCL11A that is in linkage disequilibrium with the SNP used to discover its relevance to HbF expression are needed to address these questions. The findings of Sankaran et al. also have potential consequences for developing new therapies to treat sickle cell disease and other hemoglobinopathies. The inverse correlation between BCL11A and HbF expression, combined with the known ameliorative effect of HbF on the pathophysiology of sickle cell disease and β-thalassemia, suggests that inhibition of BCL11A expression or function could be an effective treatment for these disorders. The study also illustrates that, when experiments are appropriately designed, the initial findings of genomewide association studies can be successfully followed up at a functional level.