title: Epigenetic control of CCR5 transcript levels in immune cells and modulation by small molecules inhibitors.
abstract: Previously, we have shown that CCR5 transcription is regulated by CREB-1. However, the ubiquitous pattern of CREB-1 expression suggests the involvement of an additional level of transcriptional control in the cell type-specific expression of CCR5. In this study, we show that epigenetic changes (i.e. DNA methylation and histone modifications) within the context of the CCR5 P1 promoter region correlate with transcript levels of CCR5 in healthy and in malignant CD4(+)  T lymphocytes as well as in CD14(+)  monocytes. In normal naïve T cells and CD14(+)  monocytes the CCR5 P1 promoter resembles a bivalent chromatin state, with both repressive and permissive histone methylation and acetylation marks. The CCR5-expressing CD14(+)  monocytes however show much higher levels of acetylated histone H3 (AcH3) compared to the non-CCR5-expressing naïve T cells. Combined with a highly methylated promoter in CD14(+)  monocytes, this indicates a dominant role for AcH3 in CCR5 transcription. We also show that pharmacological interference in the epigenetic repressive mechanisms that account for the lack of CCR5 transcription in T leukaemic cell lines results in an increase in CREB-1 association with CCR5 P1 chromatin. Furthermore, RNA polymerase II was also recruited into CCR5 P1 chromatin resulting in CCR5 re-expression. Together, these data indicate that epigenetic modifications of DNA, and of histones, contribute to the control of CCR5 transcription in immune effector cells.
authors: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors: Rutger J
authors: RJ
authors: Wierda
authors: Hedwich F
authors: HF
authors: Kuipers
authors: Marja C J A
authors: MC
authors: van Eggermond
authors: Anne
authors: A
authors: Benard
authors: Jan C
authors: JC
authors: van Leeuwen
authors: Silvia
authors: S
authors: Carluccio
authors: Sacha B
authors: SB
authors: Geutskens
authors: J Wouter
authors: JW
authors: Jukema
authors: Victor E
authors: VE
authors: Marquez
authors: Paul H A
authors: PH
authors: Quax
authors: Peter J
authors: PJ
authors: van den Elsen
mesh_terms: D065100:CCR5 Receptor Antagonists; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects* / Q000235:genetics; D019169:Jurkat Cells; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D018448:Models, Immunological; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019713:Receptors, CCR5 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D065100:CCR5 Receptor Antagonists; C115163:CREB1 protein, human; C497410:CREM protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D006657:Histones; D020033:Protein Isoforms; D012333:RNA, Messenger; D019713:Receptors, CCR5; D054852:Small Molecule Libraries; D051786:Cyclic AMP Response Element Modulator