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... Show morePreviously, 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 leukemic cell lines results in an increase in CREB-1 association with the 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. Show less
Putten, C. van der; Kuipers, H.F.; Burm, S.M.; Zuiderwijk-Sick, E.A.; Straalen, L. van; Kondova, I.; ... ; Bajramovic, J.J. 2011
Activation of microglia, the macrophages of the central nervous system, is a key element in multiple sclerosis (MS) lesion development and is characterized by enhanced expression of both classes of... Show moreActivation of microglia, the macrophages of the central nervous system, is a key element in multiple sclerosis (MS) lesion development and is characterized by enhanced expression of both classes of major histocompatibility complex (MHC) molecules. This enhanced expression results from increased levels of several transcription factors involved in MHC gene expression. In addition, microglial activation in MS is characterized by enhanced motility. We show that the expression of the chemokine receptor CCR5, a mediator of cell movement, is increased on microglia, macrophages and astrocytes in MS lesions. Additionally, we have determined that CCR5 transcription is regulated by the transcription factor CREB-1, which is also involved in MHC gene expression, and is highly expressed in MS lesions. Because of their immunomodulatory properties, statins (cholesterol lowering drugs) are recently being considered as a possible treatment for MS. We have determined that statins decrease expression of amongst others MHC and CCR5 molecules by inhibiting the transport of these molecules to the cell surface. In addition, we show that statins reduce the motility of microglia and inhibit the differentiation of blood-derived monocytes into dendritic cells, indicating that statins indeed affect critical immune functions and might prove to be beneficial for treatment of MS patients. Show less
