A minigene containing four discrete <i>cis</i> elements recapitulates GATA‐1 gene expression <i>in vivo</i>

Ohneda, Kinuko; Shimizu, Ritsuko; Nishimura, Shigeko; Muraosa, Yasushi; Takahashi, Satoru; Engel, James Douglas; Yamamoto, Masayuki

doi:10.1046/j.1365-2443.2002.00595.x

Cited by 48 publications

(59 citation statements)

References 22 publications

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“…The G1HRD can recapitulate Gata1 gene expression sufficiently enough to sustain embryonic and adult hematopoiesis (29,30). This can also be achieved by a 1-kb artificial mini-gene composed of the IE exon and four discrete cis-regulatory elements within the G1HRD (31). Substantiating these findings, our study showed that hemizygous males with congenital deletion of the IE exon die in utero.…”

Section: Discussionsupporting

confidence: 64%

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

Shimizu

Kikuchi

et al. 2010

Journal of Biological Chemistry

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GATA1 is essential for the differentiation of erythroid cells and megakaryocytes. The Gata1 gene is composed of multiple untranslated first exons and five common coding exons. The erythroid first exon (IE exon) is important for Gata1 gene expression in hematopoietic lineages. Because previous IE exon knockdown analyses resulted in embryonic lethality, less is understood about the contribution of the IE exon to adult hematopoiesis. Here, we achieved specific deletion of the floxed IE exon in adulthood using an inducible Cre expression system. In this conditional knock-out mouse line, the Gata1 mRNA level was significantly down-regulated in the megakaryocyte lineage, resulting in thrombocytopenia with a marked proliferation of megakaryocytes. By contrast, in the erythroid lineage, Gata1 mRNA was expressed abundantly utilizing alternative first exons. Especially, the IEb/c and newly identified IEd exons were transcribed at a level comparable with that of the IE exon in control mice. Surprisingly, in the IE-null mouse, these transcripts failed to produce full-length GATA1 protein, but instead yielded GATA1 lacking the N-terminal domain inefficiently. With low level expression of the short form of GATA1, IE-null mice showed severe anemia with skewed erythroid maturation. Notably, the hematological phenotypes of adult IE-null mice substantially differ from those observed in mice harboring conditional ablation of the entire Gata1 gene. The present study demonstrates that the IE exon is instrumental to adult erythropoiesis by regulating the proper level of transcription and selecting the correct transcription start site of the Gata1 gene.

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Section: Discussionsupporting

confidence: 64%

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

Shimizu

Kikuchi

et al. 2010

Journal of Biological Chemistry

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“…A number of studies have addressed the regulatory mechanisms by which Gata1 gene expression is regulated through the use of a G1HRD-based b-galactosidase reporter transgenic mouse system. These analyses have revealed the existence of multiple cis-regulatory elements that confer lineage-and stage-specific Gata1 gene expression [14,20,26,27].…”

Section: Sequences and Mechanisms That Regulate Gata1 Transcriptionmentioning

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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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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“…Of interest, GATA-1 is also expressed as distinct mRNA isoforms in blood cells and testis under the control of two alternative promoters (Ito et al, 1993). While GATA-1 expression in hematopoietic tissues is under the control of the combination of the GATA-1 site and three other distinct regulatory elements (Tsai et al, 1991;Ohneda et al, 2002), the regulatory mechanisms for GATA-1 expression in testis remains to be defined. The possibility that a distinct regulatory network regulates HEMGN expression in testis is suggested by the observation that the 5Ј upstream sequence of the HEMGN-t exon 1t contains binding sites for the Sox-5 transcription factor, which is highly expressed in round spermatids (Denny et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Alternative promoters and polyadenylation regulate tissue‐specific expression of Hemogen isoforms during hematopoiesis and spermatogenesis

Yang

Heng

Wan

et al. 2003

Developmental Dynamics

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Hemogen is a nuclear protein encoded by HEMGN (also known as hemogen in mouse, EDAG in human and RP59 in rat). It is considered to be a hematopoiesis-specific gene that is expressed during the ontogeny of hematopoiesis. Herein, we characterize two distinct splicing variants of HEMGN mRNA with restricted expression to hematopoietic cells and to round spermatids in the testis, respectively. Expression of the testis-specific HEMGN mRNA (HEMGN-t) is developmentally regulated and is concurrent with the first wave of meiosis in prepuberal mice. Sequence analysis reveals that HEMGN-t and the hematopoietic HEMGN mRNA (HEMGN-h) share a common coding sequence with distinct 5 and 3 untranslated regions and that these two isoforms are transcribed from the same gene locus, HEMGN, through the use of alternative promoters and polyadenylation sites. Thus, HEMGN expression exemplifies a developmental regulatory mechanism by which the diversification of gene expression is achieved through using distinct regulatory sequences in different cell types. Moreover, the existence of a testis-specific isoform of HEMGN suggests a role in spermatogenesis. Finally, fluorescence in situ hybridization demonstrates that HEMGN is localized to chromosome 4 A5-B2 in mouse and to chromosome 9q22 in human, which is a region known to harbor a cluster of leukemia breakpoints. Developmental Dynamics 228:606 -616, 2003.

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A minigene containing four discrete cis elements recapitulates GATA‐1 gene expression in vivo

Cited by 48 publications

References 22 publications

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

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

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

Alternative promoters and polyadenylation regulate tissue‐specific expression of Hemogen isoforms during hematopoiesis and spermatogenesis

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