Oxysterol-induced binding of NR1H2,3:RXR to the ABCG1 gene

Stable Identifier
Homo sapiens
Oxysterol-induced binding of LXR:RXR to the ABCG1 gene
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The ATP binding cassette transporter G1 (ABCG1, formerly called “white” and/or ABC8) exhibits a tissue-specific expression pattern with high expression levels found in macrophage/microglia, lung, brain, spleen, adrenal gland, heart and liver (Croop JM et al 1997; Klucken J et al. 2000). The ABCG1 gene is transcriptionally activated by cholesterol-loading and agonists of liver X receptors (LXRα/NR1H3 and LXRβ/NR1H2) and retinoid X receptors (RXRs) and has been implicated in the efflux of cholesterol to high density lipoprotein (HDL) (Venkateswaran A et al. 2000; Kennedy MA et al. 2001; Ayaori M et al. 2012; Sabol SL et al. 2005; Jakobsson T et al. 2009). Beyond a role in cellular lipid homeostasis, ABCG1 participates in glucose and lipid metabolism by controlling the secretion and activity of insulin and lipoprotein lipase (Olivier M et al. 2012; Sturek JM et al. 2010; Hardy LM et al. 2017). ABCG1 gene has been mapped to chromosome 21q22.3 and multiple human ABCG1 transcripts have been detected resulting from different transcription initiation and alternative mRNA splicing (Croop JM et al 1997; Langmann T et al. 2000; Lorkowski S et al. 2001; Kennedy MA et al. 2001). Although discrepancies were initially found among reports in the literature regarding the structure of the ABCG1 gene, it is now established that the ABCG1 gene is composed of 23 exons encoding a protein that forms a half transporter with 6 transmembrane spanning domains and a single intracellular nucleotide binding domain (NBD) (Langmann T et al. 2000; Kennedy MA et al. 2001; Hardy LM et al. 2017). This NBD domain contains highly conserved Walker A and Walker B motifs and is required for the binding and the hydrolysis of ATP which might provide required energy to transport substrates across the membrane (Cserepes J et al. 2004; Hirayama H et al. 2013; Vaughan AM & Oram JF 2005). Induction of ABCG1 expression by LXR agonists likely involves the presence of multiple LXR response elements (LXRE) throughout the ABCG1 gene (Kennedy MA et al. 2001; Sabol SL et al. 2005; Uehara Y et al. 2007). Electromobility shift assays demonstrated that NR1H3 and RXR alpha bind to two LXREs in intron 7 (Kennedy MA et al. 2001). Another set of two functional LXREs, LXRE-A and LXRE-B, was identified in the first and second introns of the human ABCG1 gene (Sabol SL et al. 2005). Further, studies of the transcriptional activity of truncated human ABCG1 promoter constructs showed that the NR1H2,3:RXR response region (or LXRE) is located in the human ABCG1 promoter A (LXRE-A) between -303 and -233 (Uehara Y et al. 2007).

G-protein pathway suppressor 2 (GPS2) was identified as a co-regulator required for NR1H2,3-induced transcription of the ABCG1 gene in human hepatic HepG2 and macrophage THP-1 cells (Jakobsson T et al. 2009). In macrophages, silencing of GPS2 by RNA interference reduced ABCG1 expression and diminished ABCG1-mediated cholesterol efflux. Chromatin immunoprecipitation analysis and 2-hybrid and protein-protein interaction assays revealed that GPS2 interacted with NR1H2,3:RXR heterodimer at the LXRE of the ABCG1 promoter (Jakobsson T et al. 2009). Chromosome conformation capture assays using the human hepatoma cell line, Huh7, transfected with GPS2-targeting siRNAs showed that GPS2 was required for intrachromosomal communication of the ABCG1 promoter and enhancer triggered by NR1H2,3 activation (Jakobsson T et al. 2009). Further, ligand activation of NR1H2,3 induced two functionally coupled GPS2-dependent processes: (1) receptor recruitment to an ABCG1 promoter/enhancer unit and (2) lysine-specific histone demethylase 1 (KDM1)-dependent H3K9 demethylation (Jakobsson T et al. 2009). The model suggests that the H3K9 methylation imposes a chromatin barrier at certain genomic loci (e.g., ABCG1) that prevents nuclear receptors (NR) (e.g., NR1H2,3) from high-affinity DNA binding (as detected by ChIP assays). Ligand activation in vivo triggers recruitment of KDMs to NRs (in the case of NR1H2,3 via GPS2), thereby facilitating H3K9 demethylation and high-affinity DNA binding (Jakobsson T et al. 2009).

Literature References
PubMed ID Title Journal Year
19481530 GPS2 is required for cholesterol efflux by triggering histone demethylation, LXR recruitment, and coregulator assembly at the ABCG1 locus

Jakobsson, T, Gustafsson, JA, Steffensen, KR, Sanyal, S, Lou, X, Ehrlund, A, Toresson, G, Venteclef, N, Treuter, E, Damdimopoulos, AE

Mol. Cell 2009
28869506 Critical Role of the Human ATP-Binding Cassette G1 Transporter in Cardiometabolic Diseases

Le Goff, W, Frisdal, E, Hardy, LM

Int J Mol Sci 2017
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