Concise Review: Epigenetic Regulation of Hematopoiesis: Biological Insights and Therapeutic Applications

Abstract

Hematopoiesis is the process of blood cell formation starting from hematopoietic stem/progenitor cells (HSPCs). The understanding of regulatory networks involved in hematopoiesis and their impact on gene expression is crucial to decipher the molecular mechanisms that control hematopoietic development in physiological and pathological conditions, and to develop novel therapeutic strategies. An increasing number of epigenetic studies aim at defining, on a genome-wide scale, the cis-regulatory sequences (e.g., promoters and enhancers) used by human HSPCs and their lineage-restricted progeny at different stages of development. In parallel, human genetic studies allowed the discovery of genetic variants mapping to cis-regulatory elements and associated with hematological phenotypes and diseases. Here, we summarize recent epigenetic and genetic studies in hematopoietic cells that give insights into human hematopoiesis and provide a knowledge basis for the development of novel therapeutic approaches. As an example, we discuss the therapeutic approaches targeting cis-regulatory regions to reactivate fetal hemoglobin for the treatment of β-hemoglobinopathies. Epigenetic studies allowed the definition of cis-regulatory sequences used by human hematopoietic cells. Promoters and enhancers are targeted by transcription factors and are characterized by specific histone modifications. Genetic variants mapping to cis-regulatory elements are often associated with hematological phenotypes and diseases. In some cases, these variants can alter the binding of transcription factors, thus changing the expression of the target genes. Targeting cis-regulatory sequences represents a promising therapeutic approach for many hematological diseases. Stem Cells Translational Medicine 2017;6:2106-2114.

Keywords: Anemia; Epigenetics; Hematopoiesis; Transcriptional regulation.

Figure 1

The current model of human hematopoiesis. Schematic representation of the hematopoietic hierarchical tree, composed of multipotent, oligopotent, and unipotent cell types. Abbreviations: B, B cells; Baso, basophils; CLP, common lymphoid progenitor; CMP, common myeloid progenitor; DC, dendritic cells; Eos, eosinophils; Ery, erythrocytes; GMP, granulocyte/macrophage progenitor; HSC, hematopoietic stem cell; MC, mast cells; MEP, megakaryocyte/erythroid progenitor; Mk/Pla, megakaryocytes/platelets; MLP, multilymphoid progenitor; M/M, monocytes/macrophages; MPP, multipotent progenitor cell; Neutr, neutrophils; NK, natural killer cells; T, T cells.

Figure 2

Genetic variants in cis‐regulatory elements affect target gene expression. Genetic variants mapping to enhancers or promoters (indicated by yellow and blue stars, respectively) can prevent the binding of transcription factors and result in decreased expression of the target genes (e.g., CCND3, CEBPA, ALAS2, UROS, PKLR, and HBD). Active enhancers are characterized by H3K4me1 and H3K27ac histone marks, whereas H3K27ac and H3K4me3 mark active promoters. Abbreviations: prom, promoter; enh, enhancer; TF, transcription factor.

Figure 3

Genetic variants in the β‐globin locus, HBS1L‐MYB, and BCL11A loci influence fetal hemoglobin (HbF) levels. (A): Schematic representation of the β‐globin locus on chromosome 11. Point mutations (HPFH −175 T > C and HPFH −198 T > C upstream of the γ‐globin transcription start sites [TSSs]) and deletions (HPFH 13‐bp in ^Aγ‐globin promoter and HPFH‐5) are associated with HPFH. The −175 T > C and −198 T > C mutations create binding sites for TAL1 and KLF1 transcriptional activators. A common SNP at position −158 bp of the ^Gγ‐globin promoter is associated with moderately high levels of HbF. LCR and β‐like globin genes (embryonic ɛ, fetal ^Aγ and ^Gγ, and adult δ and β) are indicated. (B): The region between HBS1L and MYB genes on chromosome 6 contains three HMIP blocks 1, 2, and 3. Five SNPs associated with higher HbF levels map to the −84 and −71 kb MYB enhancers in HMIP‐2. These variants reduce LDB1, GATA1, and KLF1 occupancy, thus decreasing MYB expression and, as a consequence, increasing HbF expression. (C): Representation of the BCL11A gene on chromosome 2. Several SNPs, associated with high HbF levels map to three erythroid‐specific intronic enhancers located 55, 58, and 62 kb downstream of the BCL11A TSS. A SNP within the +62 kb enhancer impairs GATA1 and TAL1 binding, thus leading to a reduction of BCL11A expression and increase of HbF levels. Targeted disruption of a GATA1 binding site in the +58 kb enhancer is also associated with decreased BCL11A levels and high HbF expression. Abbreviations: HMIP, HBS1L‐MYB intergenic polymorphism; HPFH, hereditary persistence of fetal hemoglobin; LCR, locus control region; SNP, single nucleotide polymorphism.