Epigenetic regulation of CIITA expression in human T-cells

• Published in: Biochemical pharmacology 2011-11, Vol.82 (10), p.1430-1437
• Main Authors: van Eggermond, Marja C.J.A., Boom, Daniël R., Klous, Petra, Schooten, Erik, Marquez, Victor E., Wierda, Rutger J., Holling, Tjadine M., van den Elsen, Peter J.
• Format: Article
• Language: English
• Subjects: Acetylation; Base Sequence; CD4-Positive T-Lymphocytes - metabolism; Cell Line; Chromatin; Class II TransActivator (CIITA); CpG Islands; DNA Methylation; DNA-directed RNA polymerase; Epigenesis, Genetic - physiology; Epigenetic regulation; epigenetics; Gene Expression Regulation - physiology; genes; histones; Histones - metabolism; Humans; Methylation; MHC class II (MHC-II); Molecular Sequence Data; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; pharmacology; Promoter Regions, Genetic; recruitment; T-cells; T-leukemia; T-lymphocytes; T-lymphoma; Trans-Activators - genetics; Trans-Activators - metabolism; transcription (genetics)
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2011.05.026

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 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.