Co-repressor complex dissociates from the transcription unit of the ABCA1 gene

Stable Identifier
R-HSA-9024334
Type
Reaction [dissociation]
Species
Homo sapiens
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In the unliganded state, NR1H2,3 (LXR):RXR heterodimers are bound to DNA response elements in association with co-repressor complexes resulting in repression of target genes such as the ATP-binding cassette transporter (ABCA1) gene (Wagner BL et al. 2003; Jakobsson T et al. 2009). Ligand binding to NR1H2,3 induces conformational changes leading to release of co-repressor complexes and recruitment of co-activator complexes and transcription of target genes. A mammalian two-hybrid analysis, using GAL4 fusions of the receptor interacting domains (ID) from the nuclear receptor corepressor (NCOR1) and the silencing mediator of retinoic acid and thyroid hormone receptors (SMRT, also known as NCOR2) transiently co-expressed with VP-16 fusions of NR1H3 or NR1H2 ligand binding domains in the monkey kidney fibroblasts CV-1 cells showed that in the absence of ligand, both NR1H2 and NR1H3 interacted with the corepressor IDs of NCOR and SMRT (Wagner BL et al. 2003). Biochemical work has identified a core complex consisting of NCOR, histone deacetylase 3 (HDAC3), transducin β-like proteins (TBL1, TBLR1), and G protein pathway suppressor 2 (GPS2) (Zhang J et al. 2002). Chromatin immunoprecipitation (ChIP) assays in HepG2 cells revealed that, in the absence of GW3965, a synthetic NR1H2,3 agonist, NCOR and HDAC3 were associated with the ABCA1 promoter, while agonist treatment caused their dissociation and induced recruitment of histone acetyltransferase (HAT) CBP and RNA polymerase II (Jakobsson T et al. 2009). TBLR1 was also present at the promoter and unaffected by the ligand status. GPS2 was found to occupy the ABCA1 promoter in the absence of ligand but was released upon GW3965 treatment, while NR1H2,3 (LXR) recruitment was observed already in the absence of ligand and further enhanced upon ligand activation (Jakobsson T et al. 2009). The inclusion of anti-RXR antibody in the re-ChIP assays demonstrates that GPS2 associates with the LXR:RXR heterodimer. Importantly, similar recruitment patterns were obtained in human THP-1 macrophages. Thus, at the ABCA1 promoter, NR1H2,3 ligand triggers exchange of a GPS corepressor complex (containing NCoR, HDAC3, TBLR1) for the coactivator complex devoid of GPS2 (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, Venteclef, N, Toresson, G, Damdimopoulos, AE, Ehrlund, A, Lou, X, Sanyal, S, Steffensen, KR, Gustafsson, JA, Treuter, E

Mol. Cell 2009
22541735 Liver X receptor biology and pharmacology: new pathways, challenges and opportunities

Jakobsson, T, Treuter, E, Gustafsson, JA, Steffensen, KR

Trends Pharmacol. Sci. 2012
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