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

Valid Presumption of Shiga Toxin-Mediated Damage of Developing Erythrocytes in EHEC-Associated Hemolytic Uremic Syndrome

“…Importantly, epigenetic modifications directly shape HSC developmental pathways, including the cellular maintenance of self-renewal and multilineage potential, lineage commitment, and aging [ 19 , 20 ]. Unraveling the molecular mechanisms that govern hematopoietic development in physiological and pathological conditions requires knowledge of the hematopoietic regulatory networks and their implication in gene expression to develop novel therapeutic concepts in regenerative medicine [ 21 , 22 ]. However, even key mechanisms such as DNA methylation, histone modifications, or non-coding RNAs inference underlying these modifications in the human genome are far from being fully understood [ 20 ].…”

Epigenetics in a Spectrum of Myeloid Diseases and Its Exploitation for Therapy

“…In the next section, we only discuss the function of those epigenetic regulators that are recurrently mutated in CHIP, MDS and AML. For more detail and further reading on the role of other epigenetics in hematopoiesis, we would like to point towards several recent reviews from colleagues [ 38 , 39 , 40 ].…”

ATF4 Regulates MYB to Increase γ-Globin in Response to Loss of β-Globin

“…MYB is a known regulator of HbF expression at multiple levels, including promotion of BCL11A expression. (Antoniani et al, 2017). MYB transcript levels were reduced in cells with HBB knockout or harboring an ATF4 mutation.…”