A regulatory network governing Gata1 and Gata2 gene transcription orchestrates erythroid lineage differentiation

Abstract

GATA transcription factor family members GATA1 and GATA2 play crucial roles in the regulation of lineage-restricted genes during erythroid differentiation. GATA1 is indispensable for survival and terminal differentiation of erythroid, megakaryocytic and eosinophilic progenitors, whereas GATA2 regulates proliferation and maintenance of hematopoietic stem and progenitor cells. Expression levels of GATA1 and GATA2 are primarily regulated at the transcriptional level through auto-and reciprocal regulatory networks formed by these GATA factors. The dynamic and strictly controlled change of expression from GATA2 to GATA1 during erythropoiesis has been referred to as GATA factor switching, which plays a crucial role in erythropoiesis. The regulatory network comprising GATA1 and GATA2 gives rise to the stage-specific changes in Gata1 and Gata2 gene expression during erythroid differentiation, which ensures specific expression of early and late erythroid genes at each stage. Recent studies have also shed light on the genome-wide binding profiles of GATA1 and GATA2, and the significance of epigenetic modification of Gata1 gene during erythroid differentiation. This review summarizes the current understanding of network regulation underlying stagedependent Gata1 and Gata2 gene expressions and the functional contribution of these GATA factors in erythroid differentiation.

Development and differentiation of the erythroid lineage in mammals

“…These two transcription factors display reciprocal expression profiles during erythropoiesis and play different roles in erythroid development: GATA-2 regulates proliferation and maintenance of erythroid and hematopoietic progenitors, while GATA-1 promotes differentiation (Bresnick et al, 2012; Fujiwara et al, 2004; Moriguchi and Yamamoto, 2014; Tsai et al, 1994). GATA-2 is a transactivator of Gata-1 during erythroid progenitor expansion (Bresnick et al, 2012; Cantor, 2005; Ferreira et al, 2005).…”

Establishment of a Screening System to Identify Novel GATA-2 Transcriptional Regulators

“…During erythroid differentiation, GATA-2 levels concomitantly decrease with increased GATA-1 levels (Bresnick et al 2010). Based on a murine model of erythroid differentiation, GATA-1 represses GATA-2 transcription by displacing GATA-2 from sites at −77, −3.9, −2.8, −1.8, and +9.5 kb relative to the 1S promoter, each of which is considered as "GATA switch site" (Bresnick et al 2010;Moriguchi et al 2014). Among these enhancers, deletion of the +9.5 site involving GATAbinding motif leads to delayed embryonic lethality compared with global Gata2 knockout (Johnson et al 2012).…”

Progenitor Stage-Specific Activity of a cis-Acting Double GATA Motif for Gata1 Gene Expression

“…ATA1 is a member of the GATA zinc finger transcription factor family and plays a central role in erythropoiesis (1)(2)(3). GATA1 expression starts at common myeloid progenitor (CMP) stage, and the expression level increases when erythroid lineage cells differentiate into the proerythroblast stage (4,5).…”

“…This dynamic change in GATA1 expression is essential for erythropoiesis, since constitutive expression of GATA1 at a high level under the regulation of the human ␤-globin gene in transgenic mice is lethal due to defective erythroid cell maturation (6). A series of studies have revealed that the Gata1 gene is regulated through the activity of multiple cisregulatory elements (1)(2)(3). However, the precise contribution of each cis-element to Gata1 expression in specific hematopoietic lineages and differentiation stages has not been fully understood.…”

“…Meanwhile, many issues still remain unsolved with regard to the upstream promoter region of the Gata1 gene, containing a palindromic double GATA (dbGATA) motif located 680 bp 5= to the IE transcriptional start site (1,13). This palindromic dbGATA motif retains 8-fold-higher binding affinity to GATA1 than does a single GATA motif (14,15).…”