GATA Proteins Work Together with Friend of GATA (FOG) and C-terminal Binding Protein (CTBP) Co-regulators to Control Adipogenesis

Briony H.A Jack,Merlin Crossley

doi:10.1074/jbc.m110.141317

Abstract

GATA transcription factors have been implicated in controlling adipogenesis in Drosophila and in mammals. In mammals, both GATA2 and GATA3 have been shown to be present in preadipocytes, and their silencing allows the onset of adipogenesis. Overexpression of GATA proteins blocks adipogenesis in cellular assays. GATA factors have been found to operate through recruiting cofactors of the Friend of GATA (FOG) family. FOG proteins, in turn, recruit co-regulators, including C-terminal binding proteins (CTBPs). We have investigated whether FOGs and CTBPs influence adipogenesis. We found that both FOG1 and FOG2 are expressed in cells prior to adipogenesis but are down-regulated as adipogenesis proceeds. Overexpression of FOG1 or FOG2 interferes with adipogenesis. Mutant versions of FOG2 unable to bind CTBP or GATA proteins are impaired in their inability to inhibit adipogenesis. Finally, a mutant version of GATA2, unable to associate with FOGs, also displays abnormal activity and causes enhanced cell proliferation. These results implicate FOGs and CTBPs as partners of GATA proteins in the control of adipocyte proliferation and differentiation.

Highlights

The molecular processes that control the development of adipose tissue are being intensively investigated
We have found that whereas C-terminal binding proteins (CTBPs) is present throughout adipogenesis, FOG1 and FOG2, like GATA proteins, are down-regulated as adipogenesis proceeds
Expression of Friend of Gata Genes Is Regulated during Adipogenesis—We first investigated whether Fog1 and Fog2 mRNA were present in 3T3-L1 cells and whether their levels were dynamically regulated during differentiation

Summary

Introduction

The molecular processes that control the development of adipose tissue are being intensively investigated. After preadipocytes receive a stimulus to differentiate, two members of the CCAAT/enhancer-binding protein family of transcription factors, C/EBP␤ and C/EBP␦, are activated. They in turn activate the expression of C/EBP␣ and the nuclear receptor peroxisome proliferator-activated receptor ␥ (PPAR␥) [1]. Initial studies in Drosophila revealed that the GATA family member Serpent was necessary for fat cell development [5, 6] In mammals, both GATA2 and GATA3 were found to be highly expressed in preadipocytes, their levels declined as adipogenesis began, and their overexpression inhibited adipocyte differentiation [3]. CTBPs recruit a number of histone-modifying enzymes, including deacetylases and methyltransferases, and thereby functionally contribute to gene silencing [16]

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