Loss of the Gata1 Gene IE Exon Leads to Variant Transcript Expression and the Production of a GATA1 Protein Lacking the N-terminal Domain

Kobayashi, Eri; Shimizu, Ritsuko; Kikuchi, Yūko; Takahashi, Satoru; Yamamoto, Masayuki

doi:10.1074/jbc.m109.030726

Cited by 12 publications

(14 citation statements)

References 48 publications

(61 reference statements)

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“…1a). Seven highly conserved GATA motifs, and two alternative transcription start sites (IE b and IE c ), are also identified in this region [15].…”

Section: Sequences and Mechanisms That Regulate Gata1 Transcriptionmentioning

confidence: 99%

“…1a) [6,13,14]. The proximal IE exon directs Gata1 expression in hematopoietic cells [13,15], while the distal IT exon primarily directs Gata1 expression in testicular Sertoli cells [16,17]. The regulation of Gata1 gene was initially studied using erythroid cell lines, MEL and K562 [18,19], and was subsequently studied in greater detail through in vivo transgenic reporter mouse approaches [14,20].…”

Section: Gata1 Gene Structure and Gata1 Hematopoietic Regulatory Domainmentioning

confidence: 99%

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

Moriguchi

Yamamoto

2014

Int J Hematol

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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.

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“…1a). Seven highly conserved GATA motifs, and two alternative transcription start sites (IE b and IE c ), are also identified in this region [15].…”

Section: Sequences and Mechanisms That Regulate Gata1 Transcriptionmentioning

confidence: 99%

Section: Gata1 Gene Structure and Gata1 Hematopoietic Regulatory Domainmentioning

confidence: 99%

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

Moriguchi

Yamamoto

2014

Int J Hematol

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“…6A and B). Chromatin regions enriched for H4Ac are known to be transcriptionally active/permissive loci, and those enriched for H3K4me2 are known to preferentially mark transcriptionally active regions (30,31).…”

Section: Resultsmentioning

confidence: 99%

“…The 1st-intron element contains evolutionarily conserved multiple GATA motifs (8,31). As summarized in Fig.…”

Section: Discussionmentioning

confidence: 99%

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

Moriguchi

Suzuki

et al. 2015

Molecular and Cellular Biology

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GATA1 is a master regulator of erythropoiesis, expression of which is regulated by multiple discrete cis-acting elements. In this study, we examine the activity of a promoter-proximal double GATA (dbGATA) motif, using a Gata1 bacterial artificial chromosome (BAC)-transgenic green fluorescent protein (GFP) reporter (G1BAC-GFP) mouse system. Deletion of the dbGATA motif led to significant reductions in GFP expression in hematopoietic progenitors, while GFP expression was maintained in erythroblasts. Consistently, in mice with a germ line deletion of the dbGATA motif (Gata1 ⌬dbGATA mice), GATA1 expression in progenitors was significantly decreased. The suppressed GATA1 expression was associated with a compensatory increase in GATA2 levels in progenitors. When we crossed Gata1 ⌬dbGATA mice with Gata2 hypomorphic mutant mice (Gata2 fGN/fGN mice), the Gata1 ⌬dbGATA ::Gata2 fGN/fGN compound mutant mice succumbed to a significant decrease in the progenitor population, whereas both groups of single mutant mice maintained progenitors and survived to adulthood, indicating the functional redundancy between GATA1 and GATA2 in progenitors. Meanwhile, the effects of the dbGATA site deletion on Gata1 expression were subtle in erythroblasts, which showed increased GATA1 binding and enhanced accumulation of active histone marks around the 1st-intron GATA motif of the ⌬dbGATA locus. These results thus reveal a novel role of the dbGATA motif in the maintenance of Gata1 expression in hematopoietic progenitors and a functional compensation between the dbGATA site and the 1st-intron GATA motif in erythroblasts. GATA1 is a member of the GATA zinc finger transcription factor family and plays a central role in erythropoiesis (1-3). 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). From the proerythroblast stage onward, the GATA1 expression level decreases as red blood cells mature. 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 (1-3). However, the precise contribution of each cis-element to Gata1 expression in specific hematopoietic lineages and differentiation stages has not been fully understood.The murine Gata1 locus is composed of two alternative noncoding first exons, IT and IE, and five coding exons, II to VI. The distal IT promoter specifies Gata1 gene expression in testicular Sertoli cells, whereas the proximal IE promoter directs gene expression in hematopoietic lineage cells (7). We have demonstrated by transgenic reporter mouse assays that an 8-kb region covering from 3.9 kb upstream of the IE exon to the 2nd exon contains sufficient regulatory information to direct Gata1 g...

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“…An additional line of GATA1-deficient mice (referred to as Gata1 ΔIE ) has been produced by a conditional deletion of the promoter/first exon of the Gata1 gene [57]. The conditional adult Gata1 ΔIE mice also suffer from anemia.…”

Section: Leukemogenesis Caused By Gata1 Deficiencymentioning

confidence: 99%

Leukemogenesis in Down syndrome

Shimizu¹,

Yamamoto²

2015

Health Problems in Down Syndrome

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The incidence of leukemia is higher in Down syndrome children than that in the general population, while the risk of solid tumors is significantly reduced in Down syndrome. Recent studies utilizing mouse models have shown that distinct mechanisms caused by the elevated dosage of multiple genes is implicated in the protection from tumor progression depending on the type of solid neoplasm. In contrast, increased incidence of mutation in the several specific genes is reported as a cause of the onset of leukemias. Especially, acquired mutations in the GATA1 gene are associated with leukemogenesis of megakaryoblastic leukemia (AMKL) and transient myeloproliferative disorder (TMD) related to Down syndrome. The mutations are clustered in the region corresponding to the N-terminal domain of GATA1 and result in the production of the short form of GATA1 (GATA1-S), which utilizes Met84 as an alternative translation initiation codon. Efforts producing mouse models of Down TMD and AMKL have been undertaken, as these models seem to provide important insights into the pathogenesis of multistep leukemogenesis. Concomitantly, the function of GATA1 has been examined extensively, and the analyses present a prototype for the study of lineage-restricted transcription factors that play an essential role for the differentiation, proliferation, and apoptosis of erythroid cells, megakaryocytes, mast cells, and eosinophils. In this chapter, we will summarize recent progress in the studies of leukemias that occur in Down syndrome, especially in relation to GATA1 mutations.

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Loss of the Gata1 Gene IE Exon Leads to Variant Transcript Expression and the Production of a GATA1 Protein Lacking the N-terminal Domain

Cited by 12 publications

References 48 publications

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

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

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

Leukemogenesis in Down syndrome

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