Gata Transcription Factors Proteins


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 Gata Transcription Factors Proteins Background

The GATA family of transcription factors is named for their ability to bind DNA at a cognate DNA sequence (A/T)GATA(A/G). They do so via two homologous zinc finger domains, each of which bears the signature sequence Cys-X2-Cys-X17- Cys-X2-Cys. Though similar in sequence, discrete functions have been ascribed to each zinc finger. The C-terminal zinc finger is indispensable for DNA-binding, while the N-terminal zinc finger is required for transcriptional activation, presumably by stabilizing the DNA-protein complex. GATA-1, the founding member of the GATA protein family, positively regulates transcription of most erythroid-specific genes by binding to the promoter regions of such genes. Experiments conducted in chimeric mice derived from GATA-1-/- embryonic stem cells indicate that GATA-1 is necessary for full differentiation of the erythroid lineage, suggesting a crucial role for GATA-1 in this process, possibly as early as during commitment of an unspecified erythroid precursor to the erythroid lineage. Since its discovery, five other GATA proteins have been identified in vertebrates and orthologs exist in invertebrates as well. The sequences of these related proteins are conserved predominantly in the two zinc finger domains as well as the consecutive basic domain following them; outside of this region they bear little resemblance to each other in amino acid sequence. They function as transcription factors in a broad range of settings, which also include non-hematopoietic cells, and have been demonstrated to regulate both differentiation and cell fate determination. GATA-1, -2, and -3 have been identified in various hematopoietic cell types, and can negatively or positively regulate genes specific to the hematopoietic lineages in which they are expressed. Similarly, GATA-4, -5, and -6 are expressed primarily in the heart and gut, and activate genes in tissues derived from the gut endoderm.

The GATA ortholog serpent is necessary for formation of the midgut endoderm in Drosophila and is expressed in the developing foregut and hindgut known as the fat body. In Drosophila, this primitive organ is the functional analog of the mammalian immune system, liver, and energy storage. In addition, the Drosophila fat body expresses many other genes that share structural or functional homology with genes found in mammalian adipose tissue. This prompted us to investigate whether the Drosophila fat body is similar to mammalian adipose tissue by examining the role of GATA transcription factors in adipose tissue formation and metabolism in mammalian experimental systems.

 

GATA transcription factors in adipogenesis

Of the six GATA proteins, GATA-2 and GATA-3 are expressed abundantly in white adipose, while GATA-2 but not -3 is expressed in brown adipose tissue. Interestingly, GATA expression is restricted to early stages of preadipocyte differentiation in culture, as well as to the preadipocyte fraction but not mature adipocyte fraction of adipose tissue. This unique expression pattern suggests that transcriptional downregulation of GATA factors may be a required feature of adipogenesis. Indeed, in adipogenic cell lines, constitutive GATA expression throughout differentiation hampers expression of functionally critical genes. Ectopic GATA expression in 3T3-L1 and 3T3-F442A cells results in dramatic decreases in genes such as PPARγ and C/EBPα, as well as late adipocyte markers such as aP2 and adipsin. Along with this altered gene profile is full inhibition of lipid accumulation, as the preadipocytes expressing GATA-2 or -3 are locked into a fibroblast-like appearance. The relevance of GATA-2 and GATA-3 for metabolism is underscored by their interesting expression pattern in adipose tissue of genetically obese mouse models compared to their lean counterparts. GATA-2 and GATA-3 transcripts are less abundant in white adipose tissue of obese animals compared to age-matched lean controls from three different genetic backgrounds, which suggests that expression of GATA at inappropriately low levels (such as in white adipose tissue of obese models) contributes to obesity by removing barriers to adipocyte differentiation and turnover.

 

GATA co-factors

The recent identification of novel factors that interact with GATA also opens up new possibilities for investigating the mechanism of GATA action in adipogenesis. Friend of GATA-1 (FOG-1) is a GATA co-factor identified by a yeast two-hybrid screen of an erythroleukemia cell line (MEL) cDNA library using the N-terminal finger of GATA-1 as bait, since the requirement for the GATA-1 N-finger in erythropoiesis had previously been established. Similarly, repressor of GATA (ROG) was also identified using a yeast two-hybrid screen of a Th-2 cell cDNA library using a GATA-3 zinc finger domain as bait. Friend of GATA-2 (FOG-2) was cloned using 5’- and 3’- RACE technology with degenerate primers against a sequence encoding conserved zinc fingers of FOG-1. The essential role of FOG proteins has been demonstrated by phenotypes of animals with targeted mutations of these genes. FOG-T^’ mice die at gestational day 10.5-11.5 due to arrested erythroid maturation, similar to the pathology of GATA-1'^' mice. FOG-2-/- mice die in utero from complications arising from defective coronary structure, and knock-in mutations which render FOG-2 Incapable of Interacting with the cardiac expressed GATA factor GATA-4 result In the same phenotype. These results illustrate the need for intact FOG-GATA interactions in these developmental programs. In vivo studies of targeted mutations of ROG have not yet been reported. Since they are known to Interact with GATA factors In a variety of settings, all of these co-factors are excellent candidates for mediating the effect of GATA factors In adipogenesis, and warrant further Investigation.