Epigenetic regulation of fetal globin gene expression in adult erythroid cells

Abstract

The developmental regulation of globin gene expression has served as an important model for understanding higher eukaryotic transcriptional control mechanisms. During human erythroid development, there is a sequential switch from expression of the embryonic ε-globin gene to the fetal ɣ-globin gene in utero, and postpartum the ɣ-globin gene is silenced, as the β-globin gene becomes the predominantly expressed locus. Because the expression of normally silenced fetal ɣ-type globin genes and resultant production of fetal hemoglobin (HbF) in adult erythroid cells can ameliorate the pathophysiological consequences of both abnormal β-globin chains in sickle cell anemia and deficient β-globin chain production in β-thalassemia, understanding the complex mechanisms of this developmental switch has direct translational clinical relevance. Of particular interest for translational research are the factors that mediate silencing of the ɣ-globin gene in adult stage erythroid cells. In addition to the regulatory roles of transcription factors and their cognate DNA sequence motifs, there has been a growing appreciation of the role of epigenetic signals and their cognate factors in gene regulation, and in particular in gene silencing through chromatin. Much of the information about epigenetic silencing stems from studies of globin gene regulation. As discussed here, the term epigenetics refers to postsynthetic modifications of DNA and chromosomal histone proteins that affect gene expression and can be inherited through somatic cell replication. A full understanding of the molecular mechanisms of epigenetic silencing of HbF expression should facilitate the development of more effective treatment of β-globin chain hemoglobinopathies.

Figure 1. Mi2β-mediated epigenetic globin gene silencing through multiple mechanisms

Mi2β is a critical component of the MBD2/NuRD complex which regulates developmental globin gene silencing independently of BCL11A and KLF1/EKLF. Mi2β also binds to the distal promoter region of the γ-globin gene as part of the MBD3/NuRD/GATA-1/FOG-1 silencing complex. Importantly, Mi2β binds to and activates expression of BCL11A and KLF1/EKLF which in turn silence ɣ-globin gene expression. In each of these processes, Mi2β has been shown to directly promote ɣ-globin gene silencing. As depicted, Mi2β is also associated with the BCL11A complex and the TR2/TR4/DRED complex through its association with NuRD, but as indicated by the non-colored symbol, its role in the action of these complexes has not been demonstrated directly. Likewise, other non-colored symbols designate epigenetic modulators that have not been shown directly to mediate silencing in association with factors designated by colored symbols.

Figure 2. Interdependence of epigenetic gene silencing

Existing data suggest that DNA methylation and postsynthetic histone modification are dependent on one another and in turn reinforce each other. Either mark appears capable of establishing the other by recruiting epigenetic writer enzymes, thus resulting in a cycle that reinforces gene silencing. For example, as illustrated, DNA methylation recruits methyl cytosine binding proteins which recruit co-repressor complexes that contain histone modifying enzymes that catalyze loss of activating marks (Eg. Histone acetylation and methylation) or addition of repressive marks (Eg. Histone methylation). In turn, repressive histone modifications such as H3K9 methylation can recruit DNA methyltransferases that deposit the repressive methylation mark at CpG dinucleotides.