title: SUMOylation regulates the chromatin occupancy and anti-proliferative gene programs of glucocorticoid receptor.
abstract: In addition to the glucocorticoids, the glucocorticoid receptor (GR) is regulated by post-translational modifications, including SUMOylation. We have analyzed how SUMOylation influences the activity of endogenous GR target genes and the receptor chromatin binding by using isogenic HEK293 cells expressing wild-type GR (wtGR) or SUMOylation-defective GR (GR3KR). Gene expression profiling revealed that both dexamethasone up- and downregulated genes are affected by the GR SUMOylation and that the affected genes are significantly associated with pathways of cellular proliferation and survival. The GR3KR-expressing cells proliferated more rapidly, and their anti-proliferative response to dexamethasone was less pronounced than in the wtGR-expressing cells. ChIP-seq analyses indicated that the SUMOylation modulates the chromatin occupancy of GR on several loci associated with cellular growth in a fashion that parallels with their differential dexamethasone-regulated expression between the two cell lines. Moreover, chromatin SUMO-2/3 marks, which were associated with active GR-binding sites, showed markedly higher overlap with the wtGR cistrome than with the GR3KR cistrome. In sum, our results indicate that the SUMOylation does not simply repress the GR activity, but regulates the activity of the receptor in a target locus selective fashion, playing an important role in controlling the GR activity on genes influencing cell growth.
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, PO Box 1627, FI-70211 Kuopio, Finland, European Molecular Biology Laboratory (EMBL), Core Facilities and Services, Meyerhofstrasse 1, 69117 Heidelberg, Germany and Department of Pathology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Paakinaho
authors.forename: Sanna
authors.initials: S
authors.lastname: Kaikkonen
authors.forename: Harri
authors.initials: H
authors.lastname: Makkonen
authors.forename: Vladimir
authors.initials: V
authors.lastname: Benes
authors.forename: Jorma J
authors.initials: JJ
authors.lastname: Palvimo
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D058207:Sumoylation
chemical_list: D002843:Chromatin; D011965:Receptors, Glucocorticoid; D025841:Small Ubiquitin-Related Modifier Proteins; D003907:Dexamethasone