The zinc finger protein 202 (ZNF202) is a transcriptional repressor of ATPbinding cassette transporter A1 (ABCA1) and ABCG1 gene expression and a modulator of cellular lipid efflux

The zinc finger gene 202 (ZNF202) located within a hypoalphalipoproteinemia susceptibility locus on chromosome 11q23 is a transcriptional repressor of various genes involved in lipid metabolism. To provide further evidence fo r a functional linkage between ZNF202 and hypoalphalipoproteinemia, we inve stigated the effect of ZNF202 expression on ATP binding cassette transporte r A1 (ABCA1) and ABCG1, ABCA1 is a key regulator of the plasma high density lipoprotein pool size, whereas ABCG1 is another mediator of cellular chole sterol and phospholipid efflux in human macrophage. We demonstrate here tha t the full-length ZNF202m1 isoform binds to GnT repeats within the promoter s of ABCA1 (-229/ -210) and ABCG1 (-572/-552), ZNF202m1 expression in HepG2 cells dose-dependently repressed the promotor activities of ABCA1 and ABCG 1, This transcriptional effect required the presence of the SCAN domain in ZNF202 and the functional integrity of a TATA box at position -24 of ABCA1, whereas the presence of GnT binding motifs was nonessential. The state of ZNF202 SCAN domain oligomerization affected the ability of the adjacent ZNF 202 Kruppel-associated box domain to recruit the transcriptional corepresso r KAP1, Overexpression of ZNF202m1 in RAW264.7 macrophages prevented the in duction of ABCA1 gene expression by 20(S)OH-cholesterol and 9-cis-retinoic acid, further substantiating the interference of ZNF202 in critical element s of transcriptional activation, Finally, HDL and apoAI-mediated lipid effl ux was significantly reduced in RAW264.7 cells stably expressing ZNF202m1, In conclusion, we have identified ABCA1 and ABCG1 as target genes for ZNF20 2-mediated repression and thus, provide evidence for a functional linkage b etween ZNF202 and hypoalphalipoproteinemia.