The Pleiotropic Effects of GATA1 and KLF1 in Physiological Erythropoiesis and in Dyserythropoietic Disorders

Abstract

In the last few years, the advent of new technological approaches has led to a better knowledge of the ontogeny of erythropoiesis during development and of the journey leading from hematopoietic stem cells (HSCs) to mature red blood cells (RBCs). Our view of a well-defined hierarchical model of hematopoiesis with a near-homogeneous HSC population residing at the apex has been progressively challenged in favor of a landscape where HSCs themselves are highly heterogeneous and lineages separate earlier than previously thought. The coordination of these events is orchestrated by transcription factors (TFs) that work in a combinatorial manner to activate and/or repress their target genes. The development of next generation sequencing (NGS) has facilitated the identification of pathological mutations involving TFs underlying hematological defects. The examples of GATA1 and KLF1 presented in this review suggest that in the next few years the number of TF mutations associated with dyserythropoietic disorders will further increase.

Keywords: GATA1; KLF1; dyserythropoiesis; erythropoiesis; transcription factors.

FIGURE 1

Erythropoiesis and megakaryopoiesis are regulated at multiple levels. A complex network of extracellular signals -activating intracellular signaling pathways-, cell–cell interactions within the niche and intracellular effectors regulate cell differentiation in homeostatic conditions and in response to stress stimuli (Ferreira et al., 2005; Hattangadi et al., 2011; Songdej and Rao, 2017). These signals converge on TFs and chromatin modifiers which ultimately define the transcriptome at each given stage. The main growth factors, integrins and transcription factors involved in these processes are indicated. The GATA1 (red rectangles) and KLF1 (green rectangles) windows of expression are indicated (see also Figure 2B). HSC, Hematopoietic Stem cell; TPO, thrombopoietin; SCF, Stem cell Factor; IL, interleukin; SDF-1, stromal-derived factor-1; GPIIb/IIIa, integrins α_IIb/β₃ (CD41/CD61); EPO, erythropoietin; GCs, glucocorticoids. α₄/β₁, integrins α₄/β₁ (CD49d/CD29).

FIGURE 2

(A) Schematic structure of GATA1 and KLF1 proteins and of their DNA-binding motifs. The position of the mutations discussed in this review are indicated. ZnF, zinc fingers; TAD, transactivation domains. The DNA consensus are from the JASPAR database (http://jaspar2016.genereg.net/). (B) Phenotype of GATA1 (Pevny et al., 1991, 1995; Fujiwara et al., 1996; Shivdasani et al., 1997; Gutierrez et al., 2008) and KLF1 (Nuez et al., 1995; Perkins et al., 1995; Hodge et al., 2006; Nilson et al., 2006; Frontelo et al., 2007; Tallack and Perkins, 2010) gene knockouts in mouse.