ZNF202 is inversely regulated with its target genes ABCA1 and apoE during macrophage differentiation and foam cell formation

The zinc finger protein ZNF202 is a transcrip- tional repressor that binds to promoter elements predomi- nantly found in genes involved in lipid metabolism. Here we demonstrate that ZNF202 mRNA expression is inversely correlated with ATP binding cassette A1 (ABCA1), ABCG1, and apolipoprotein E (apoE) in human monocytes. Upregu- lation of ABCA1, ABCG1, and apoE expression during monocyte differentiation and foam cell formation was ac- companied by a simultaneous downregulation of both ZNF202 mRNA isoforms m1 and m3. Conversely, deloading of macrophage foam cells with HDL 3 caused upregulation of ZNF202 mRNA. To further characterize the transcrip- tional regulation of the ZNF202 gene, comparative genomic sequence analysis and reporter gene assays were per- formed. The ZNF202 core promoter region resides within 247 bp upstream of the transcription initiation site and is highly active in THP-1 monocytes, yet downregulated upon macrophage differentiation. Using site-directed mutagene- sis, we show that two highly conserved transcription factor binding sites, a GC-box and an Ets-binding motif, are re- quired for ZNF202 gene expression. Furthermore, electro- phoretic mobility shift assays demonstrate in vitro binding of PU.1 and GC-box binding proteins to the ZNF202 proxi- mal promoter. We conclude that the inversely correlated transcriptional activity of ZNF202 and its target genes dur- ing macrophage differentiation may reflect a direct regula- tory interdependence and thus provide further evidence for ZNF202 as an important gatekeeper of lipid efflux. — Langmann, T., C. Schumacher, S. G. Morham, C. Honer, S. Heimerl, C. Moehle, and G. Schmitz. ZNF202 is inversely regulated with its target genes ABCA1 and apoE during macrophage differentiation and foam cell formation. J. Lipid Res. 2003. 44: 968-977.