Atherosclerosis is one of the primary causes of cardiovascular disease; the number one cause of death in the western society. Atherosclerotic plaque formation is a dynamic multi-cellular process... Show moreAtherosclerosis is one of the primary causes of cardiovascular disease; the number one cause of death in the western society. Atherosclerotic plaque formation is a dynamic multi-cellular process where regulation of different genes essentially determines the activity of the different cell types involved. Gene expression is regulated, amongst others, by epigenetic processes. Epigenetic mechanisms change the accessibility of the DNA sequence and is thought to form a link between environmental factors and gene expression. Epigenetics may therefor play an important role in atherosclerosis pathology. The research described in this thesis evaluated the role of epigenetic regulation on various aspects of atherosclerosis pathology. It was found that the epigenetic H3K27Me3-mark was reduced in later stages of the disease. Monocytes differentiating into dendritic cells and macrophages (an important process in atherosclerosis pathology) showed higher transcription of the epigenetic regulatory gene KMT1c. Specifically blocking this gene resulted in reduction of DC-SIGN (a dendritic cell specific molecule) expression. By specifically blocking other epigenetic proteins, CCR5 (a molecule important to monocyte migration) was re-expressed on cells which did not express CCR5. This shows that epigenetic regulation is an important process in atherosclerosis pathology and might prove to be novel pharmacological target for treatment of atherosclerosis. Show less
Wierda, R.J.; Goedhart, M.; Eggermond, M.C.J.A. van; Muggen, A.F.; Miggelbrink, X.M.; Geutskens, S.B.; ... ; Elsen, P.J. van den 2015
This chapter describes recent advances in our understanding how epigenetic events control immune functions with emphasis on transcriptional regulation of major histocompatibility complex ClassI ... Show moreThis chapter describes recent advances in our understanding how epigenetic events control immune functions with emphasis on transcriptional regulation of major histocompatibility complex ClassI (MIC-I) and Class II (MHC-II) genes. MHC-I and MHC-II molecules play an essential role in the adaptive immune response by virtue of their ability to present peptides, respectively to CD8+ and CD4+ T cells. Central to the onset of an adequate immune response to pathogens is the presentation of pathogen-derived peptides in the context of MHC-II molecules by antigen presenting cells (APCs) to CD4+ T cells of the immune system. In particular dendritic cells are highly specialized APCs that are capable to activate naïve T cells. Given their central role in adaptive immunity, MHC-I and MHC-II genes are regulated in a tight fashion at the transcriptional level to meet with local requirements of an effective antigen-specific immune response. In these regulatory processes the MHC2TA encoded Class II transactivator (CIITA) plays a crucial role. CIITA is essential for transcriptional activation of all MHC-I genes, whereas it plays an ancillary function in the transcriptional control of MHC-I genes. The focus of this chapter therefore will be on the transcription factors that interact with conserved cis-acting promoter elements and epigenetic mechanisms that modulate cell type-specific regulation of MHC-I, MHC-I, and MHC2TA genes. Furthermore, we will also briefly discuss how genetic and epigenetic mechanisms contribute to T helper cell differentiation. Show less
Elsen, P.J. van den; Eggermond, M.C.J.A. van; Wierda, R.J.; Ballestar, E. 2011
In humans, T-cells accomplish expression of MHC-II molecules through induction of CIITA upon activation. Here we show that CIITA promoter accessibility in T-cells is epigenetically regulated. In... Show moreIn humans, T-cells accomplish expression of MHC-II molecules through induction of CIITA upon activation. Here we show that CIITA promoter accessibility in T-cells is epigenetically regulated. In unstimulated T-cells, CIITA-PIII chromatin displays relative high levels of repressive histone methylation marks (3Me-K27-H3 and 3Me-K20-H4) and low levels of acetylated histones H3 (Ac-H3) and H4 (Ac-H4). These repressive histone marks are replaced by histone methylation marks associated with transcriptional active genes (3Me-K4-H3) and high levels of Ac-H3 and Ac-H4 in activated T-cells. This is associated with concomitant recruitment of RNA polymerase II. In T-leukemia cells, devoid of CIITA expression, similar repressive histone methylation marks and low levels of acetylated histone H3 correlated with lack of CIITA expression. This in contrast to CIITA expressing T-lymphoma cells, which display high levels of Ac-H3 and 3Me-K4-H3, and relative low levels of the 3Me-K27-H3 and 3Me-K20-H4 marks. Of interest was the observation that the levels of histone acetylation and methylation modifications in histones H3 and H4 were also noted in chromatin of the downstream CIITA-PIV promoter as well as the upstream CIITA-PI and CIITA-PII promoters both in normal T-cells and in malignant T-cells. Together our data show that CIITA chromatin in T-cells expressing CIITA display similar histone acetylation and methylation characteristics associated with an open chromatin structure. The opposite is true for T-cells lacking CIITA expression, which display histone modifications characteristic of condensed chromatin. Show less
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
Aims This study was designed to investigate the counterbalancing influence of genetic variation in the promoter of the gene encoding P300/CBP associated factor (PCAF), a lysine acetyltransferase ... Show moreAims This study was designed to investigate the counterbalancing influence of genetic variation in the promoter of the gene encoding P300/CBP associated factor (PCAF), a lysine acetyltransferase (KAT), on coronary heart disease (CHD) and mortality. Methods and results The association of genetic variation in the PCAF-gene with CHD, restenosis and mortality was investigated in three large cohorts. The results were combined to examine overall effects on CHD mortality and on restenosis risk. Compared with the homozygous -2481G allele in the PCAF promoter, a significant reduction in CHD mortality risk with the homozygous -2481C PCAF promoter allele was observed. A combined risk reduction for CHD death for the three studies was 21% (15-26%; p=8.13X10(-4)). In elderly patients (> 58 years) the effects were stronger. Furthermore, this PCAF allele was significantly associated with all-cause mortality (p=0.001). Functional analysis showed that nuclear factors interact in vitro with the oligonucleotides encompassing the -2481G/C polymorphism and that this interaction might be influenced by this polymorphism in the PCAF promoter. Moreover, modulation of PCAF gene expression was detectable upon cuff-placement in an animal model of reactive stenosis. Conclusion We showed in three large prospective studies that the -2481C allele in the PCAF promoter is associated with a significant survival advantage in elderly patients. Our observations promote the concept that epigenetic processes are under genetic control and that, other than environment, variation in genes encoding KATs may also determine susceptibility to CHD outcomes and mortality. Show less
Wierda, R.J.; Geutskens, S.B.; Jukema, J.W.; Quax, P.H.A.; Elsen, P.J. van den 2010
Introduction Epigenetics explained Epigenetic alterations are reversible Atherosclerosis Epigenetics and association with atherosclerosis Epigenetic regulation of cell activity T cells Monocytes... Show moreIntroduction Epigenetics explained Epigenetic alterations are reversible Atherosclerosis Epigenetics and association with atherosclerosis Epigenetic regulation of cell activity T cells Monocytes Endothelial cells Smooth muscle cells Chemokines, their receptors and other genes involved in inflammation eNOS iNOS CCL11 (eotaxin) CCR5 Epigenetics in (vascular) inflammation KDM6B Oestrogen receptor COX2 Transcriptional regulation of MHC molecules - the role of CIITA Non-histone targets MicroRNAs Conclusions Atherosclerosis is a multifactorial disease with a severe burden on western society. Recent insights into the pathogenesis of atherosclerosis underscore the importance of chronic inflammation in both the initiation and progression of vascular remodelling. Expression of immunoregulatory molecules by vascular wall components within the atherosclerotic lesions is accordingly thought to contribute to the ongoing inflammatory process. Besides gene regulatory proteins (transcription factors), epigenetic mechanisms also play an essential and fundamental role in the transcriptional control of gene expression. These epigenetic mechanisms change the accessibility of chromatin by DNA methylation and histone modifications. Epigenetic modulators are thus critically involved in the regulation of vascular, immune and tissue-specific gene expression within the atherosclerotic lesion. Importantly, epigenetic processes are reversible and may provide an excellent therapeutic target. The concept of epigenetic regulation is gradually being recognized as an important factor in the pathogenesis of atherosclerosis. Recent research provides an essential link between inflammation and reprogramming of the epigenome. In this review we therefore discuss the basis of epigenetic regulation - and the contribution thereof in the regulation of inflammatory processes in general and during atherosclerosis in particular. Moreover we highlight potential therapeutic interventions based on epigenetic mechanisms. Show less
