A Broad Role for the Zinc Finger Protein ZNF202 in Human Lipid Metabolism

Abstract

The ZNF202 gene resides in a chromosomal region linked genetically to low high density lipoprotein cholesterol in Utah families. Here we show that the ZNF202 gene product is a transcriptional repressor that binds to elements found predominantly in genes that participate in lipid metabolism. Among its targets are structural components of lipoprotein particles (apolipoproteins AIV, CIII, and E), enzymes involved in lipid processing (lipoprotein lipase, lecithin cholesteryl ester transferase), and several genes involved in processes related to energy metabolism and vascular disease. Based on the linkage and apparent transcriptional function of ZNF202, we propose that ZNF202 is a candidate susceptibility gene for human dyslipidemia.

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

“…Interestingly, the majority of ZNF202 target genes play a critical role in HDL homeostasis. This group of genes comprises the apoA-I/C-III/A-IV/A-V gene cluster on chromosome 11, the apoE/C-I/C-IV/C-II gene cluster on chromosome 19, phospholipid transfer protein, and the enzymes lipoprotein lipase, hepatic triglyceride lipase, LCAT, and phosphatidylethanolamine N -methyltransferase (4).…”

“…This novel familial susceptibility locus for hypoalphalipoproteinemia contains the zinc finger protein ZNF202 that is functionally characterized by a SCAN (SRE-ZBP; CT-finS1; AW-1; Number 18) oligomerization domain, a Kruppel-associated box repression domain, and eight Cys 2 His 2 DNA binding motifs (4). Two splice forms have been described for ZNF202, the m1 form encoding the full-length protein, and the m3 form encoding a truncated version containing only the SCAN domain and lacking the DNA-binding motif (4). Interestingly, the majority of ZNF202 target genes play a critical role in HDL homeostasis.…”

Promoter alteration causes transcriptional repression of the POMGNT1 gene in limb-girdle muscular dystrophy type 2O

“…The influence of this transcription factor on POMGNT1 expression is supported by the strong in vitro binding of the transcriptional repressor to direct repeats of the consensus binding motif (5¢-GGGGT-3¢) in the promoter region of several genes involved in lipid metabolism, such as apolipoprotein AIV, apolipoprotein CIII and lipoprotein lipase, as well as to genes involved in blood vessel maintenance like VEGF. 16 In addition to its affinity for GnT motifs, ZNF202 can bind to GC boxes, and in our case, ZNF202 bound to direct repeats of the 5¢-GCCA-3¢ motif. Structurally, ZNF202 contains a SCAN (SRE-ZBP, CT-finS1, AW-1 and Number 18) oligomerization domain, a KRAB (Krüppel-associated box) repression domain and eight zinc-finger DNA-binding motifs.…”

“…However, ZNF202 was identified in gel shift assay using a control probe containing a previously described ZNF202 consensus sequence (ZNF202 Ctrl: Supplementary Table S2). 16 Incubation of the radiolabelled ZNF202 Dup probe with a nuclear extract generated a complex band, which was no longer evident when binding was competed by the addition of a 100-fold molar excess of cold ZNF202 Ctrl probe (Figure 4a). We also examined the endogenous expression of Sp1, Ets1, ZNF202 and the GATA-1 to GATA-6 transcription factors in the COS-7 cell line by RT-PCR, confirming that all the transcription factors analyzed, except for GATA-4, were expressed in COS-7 cells (Supplementary Figure 1).…”

Zinc Finger Protein 202, genetic variation, and HDL cholesterol in the general population

“…ZNF202 is functionally characterized by a SRE-ZBP, CT-finS1, AW-1, Number 18 (SCAN) oligomerization domain, a Krü ppel-associated box (KRAB) repression domain, and eight zinc finger (Cys 2 His 2 ) DNA binding motifs, a typical domain architecture for transcription factors (9). ZNF202 target genes are mainly involved in lipid and, particularly, HDL cholesterol metabolism (10)(11)(12), suggesting that this transcriptional repressor might be important in the determination of HDL cholesterol levels in the general population. However, it is largely unknown to what extent ZNF202 varies genetically in the general population and whether such genetic variation influences HDL cholesterol levels.…”