Abstract
The C2H2-type zinc finger protein ZNF764 acts as an enhancer for several steroid hormone receptors, and haploinsufficiency of this gene may be responsible for tissue resistance to multiple steroid hormones including glucocorticoids observed in a patient with 16p11.2 microdeletion. We examined genome-wide regulatory actions of ZNF764 on the glucocorticoid receptor (GR) in HeLa cells as a model system. ZNF764- and GR-binding sites demonstrated similar distribution in various genomic features. They positioned predominantly around 50–500 kbs from the transcription start sites of their nearby genes, and were closely localized with each other, overlapping in ~37% of them. ZNF764 demonstrated differential on/off effects on GR-binding and subsequent mRNA expression: some genes were highly dependent on the presence/absence of ZNF764, but others were not. Pathway analysis revealed that these 3 gene groups were involved in distinct cellular activities. ZNF764 physically interacted with GR at ligand-binding domain through its KRAB domain, and both its physical interaction to GR and zinc finger domain appear to be required for ZNF764 to regulate GR transcriptional activity. Thus, ZNF764 is a cofactor directing GR transcriptional activity toward specific biologic pathways by changing GR binding and transcriptional activity on the glucocorticoid-responsive genes.
Highlights
To the promoter region of glucocorticoid-responsive genes[9,14]
We found that ZNF764 and glucocorticoid receptor (GR) interact with DNA closely, and ZNF764 differentially modulates DNA-binding profiles of GR and directs its transcriptional activity toward specific biologic pathways through physical interaction
To examine genome-wide regulatory actions of ZNF764 on GR, we performed chromatin immunoprecipitation (ChIP) reactions followed by high-throughput sequencing (ChIP-Seq) using anti-GR or -ZNF764 antibody in HeLa cells transfected with control or ZNF764 small interfering RNA and treated with or without the synthetic glucocorticoid dexamethasone
Summary
SRs share some of these cofactor molecules for transcriptional regulation[15], defects in one such protein may potentially influence the transcriptional activity of several SRs, and could develop pathologies that span over multiple hormones. In agreement with this hypothesis, one family with resistance to glucocorticoids, mineralocorticoids and androgens was previously reported, with speculation of a congenital coactivator defect as a primary cause[16,17]. ZNF764 is a member of the Krüppel-type zinc finger protein (ZNF) family (KRAB-ZNF), which consists of over 800 proteins that act as DNA-binding transcriptional regulators[19]. We found that ZNF764 and GR interact with DNA closely, and ZNF764 differentially modulates DNA-binding profiles of GR and directs its transcriptional activity toward specific biologic pathways through physical interaction
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