Epigenetic Control of the Immune Escape Mechanisms in Malignant Carcinomas

ABSTRACT Downregulation of the transporter associated with antigen processing 1 (TAP-1) has been observed in many tumors and is closely associated with tumor immunoevasion mechanisms, growth, and metastatic ability. The molecular mechanisms underlying the relatively low level of transcription of the tap-1 gene in cancer cells are largely unexplained. In this study, we tested the hypothesis that epigenetic regulation plays a fundamental role in controlling tumor antigen processing and immune escape mechanisms. We found that the lack of TAP-1 transcription in TAP-deficient cells correlated with low levels of recruitment of the histone acetyltransferase, CBP, to the TAP-1 promoter. This results in lower levels of histone H3 acetylation at the TAP-1 promoter, leading to a decrease in accessibility of the RNA polymerase II complex to the TAP-1 promoter. These observations suggest that CBP-mediated histone H3 acetylation normally relaxes the chromatin structure around the TAP-1 promoter region, allowing transcription. In addition, we found a hitherto-unknown mechanism wherein interferon gamma up-regulates TAP-1 expression by increasing histone H3 acetylation at the TAP-1 promoter locus. These findings lie at the heart of understanding immune escape mechanisms in tumors and suggest that the reversal of epigenetic codes may provide novel immunotherapeutic paradigms for intervention in cancer.

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Interplay between Chromatin and trans-Acting Factors on the IME2 Promoter upon Induction of the Gene at the Onset of Meiosis

Molecular and Cellular Biology ◽

10.1128/mcb.01661-06 ◽

2006 ◽

Vol 27 (4) ◽

pp. 1254-1263 ◽

Cited By ~ 18

Author(s):

Tomomi Inai ◽

Masashi Yukawa ◽

Eiko Tsuchiya

Keyword(s):

Histone Deacetylase ◽

Chromatin Structure ◽

Molecular Basis ◽

Histone Acetyltransferase ◽

Histone H3 ◽

Repressive Chromatin ◽

Tata Element ◽

Histone H3 Acetylation ◽

Low Levels ◽

H3 Acetylation

ABSTRACT The IME2 gene is one of the key regulators of the initiation of meiosis in budding yeast. This gene is repressed during mitosis through the repressive chromatin structure at the promoter, which is maintained by the Rpd3-Sin3 histone deacetylase (HDAC) complex. IME2 expression in meiosis requires Gcn5/histone acetyltransferase, the transcriptional activator Ime1, and the chromatin remodeler RSC; however, the molecular basis of IME2 activation had not been previously defined. We found that, during mitotic growth, a nucleosome masked the TATA element of IME2, and this positioning depended on HDAC. This chromatin structure was remodeled at meiosis by RSC that was recruited to TATA by Ime1. Stable tethering of Ime1 to the promoter required the presence of Gcn5. Interestingly, Ime1 binding to the promoter was kept at low levels during the very early stages in meiosis, even when the levels of Ime1 and histone H3 acetylation at the promoter were at their highest, making a 4- to 6-h delay of the IME2 expression from that of IME1. HDAC was continuously present at the promoter regardless of the transcriptional condition of IME2, and deletion of RPD3 allowed the IME2 expression shortly after the expression of IME1, suggesting that HDAC plays a role in regulating the timing of IME2 expression.

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Promoter-specific changes in initiation, elongation and homeostasis of histone H3 acetylation during CBP/p300 inhibition

eLife ◽

10.7554/elife.63512 ◽

2021 ◽

Vol 10 ◽

Author(s):

Emily Hsu ◽

Nathan R Zemke ◽

Arnold J Berk

Keyword(s):

Rna Polymerase Ii ◽

Control Point ◽

Histone H3 ◽

Airway Epithelial Cells ◽

Proximal Region ◽

Transferase Activity ◽

Transcriptional Elongation ◽

Elongation Complex ◽

Histone H3 Acetylation ◽

H3 Acetylation

Regulation of RNA Polymerase II (Pol2) elongation in the promoter proximal region is an important and ubiquitous control point for gene expression in metazoans. We report that transcription of the adenovirus 5 E4 region is regulated during the release of paused Pol2 into productive elongation by recruitment of the super elongation complex (SEC), dependent on promoter H3K18/27 acetylation by CBP/p300. We also establish that this is a general transcriptional regulatory mechanism that applies to ~6% of expressed protein-coding genes in primary human airway epithelial cells. We observed that a homeostatic mechanism maintains promoter, but not enhancer H3K18/27ac in response to extensive inhibition of CBP/p300 acetyl transferase activity by the highly specific small molecule inhibitor A-485. Further, our results suggest a function for BRD4 association at enhancers in regulating paused Pol2 release at nearby promoters. Taken together, our results uncover processes regulating transcriptional elongation by promoter region histone H3 acetylation and homeostatic maintenance of promoter, but not enhancer, H3K18/27ac in response to inhibition of CBP/p300 acetyl transferase activity.

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The Carboxyl Terminus of Rtt109 Functions in Chaperone Control of Histone Acetylation

Eukaryotic Cell ◽

10.1128/ec.00291-12 ◽

2013 ◽

Vol 12 (5) ◽

pp. 654-664 ◽

Cited By ~ 11

Author(s):

Ernest Radovani ◽

Matthew Cadorin ◽

Tahireh Shams ◽

Suzan El-Rass ◽

Abdel R. Karsou ◽

...

Keyword(s):

Histone Acetyltransferase ◽

Histone H3 ◽

Chromatin Assembly ◽

Carboxyl Terminus ◽

Histone Chaperones ◽

Content Type ◽

Histone H3 Acetylation ◽

H3 Acetylation

ABSTRACT Rtt109 is a fungal histone acetyltransferase (HAT) that catalyzes histone H3 acetylation functionally associated with chromatin assembly. Rtt109-mediated H3 acetylation involves two histone chaperones, Asf1 and Vps75. In vivo , Rtt109 requires both chaperones for histone H3 lysine 9 acetylation (H3K9ac) but only Asf1 for full H3K56ac. In vitro , Rtt109-Vps75 catalyzes both H3K9ac and H3K56ac, whereas Rtt109-Asf1 catalyzes only H3K56ac. In this study, we extend the in vitro chaperone-associated substrate specificity of Rtt109 by showing that it acetylates vertebrate linker histone in the presence of Vps75 but not Asf1. In addition, we demonstrate that in Saccharomyces cerevisiae a short basic sequence at the carboxyl terminus of Rtt109 (Rtt109C) is required for H3K9ac in vivo . Furthermore, through in vitro and in vivo studies, we demonstrate that Rtt109C is required for optimal H3K56ac by the HAT in the presence of full-length Asf1. When Rtt109C is absent, Vps75 becomes important for H3K56ac by Rtt109 in vivo . In addition, we show that lysine 290 (K290) in Rtt109 is required in vivo for Vps75 to enhance the activity of the HAT. This is the first in vivo evidence for a role for Vps75 in H3K56ac. Taken together, our results contribute to a better understanding of chaperone control of Rtt109-mediated H3 acetylation.

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Promoter-specific changes in initiation, elongation and homeostasis of histone H3 acetylation during CBP/p300 Inhibition

10.1101/2020.09.26.315002 ◽

2020 ◽

Author(s):

E Hsu ◽

NR Zemke ◽

AJ Berk

Keyword(s):

Rna Polymerase Ii ◽

Control Point ◽

Histone H3 ◽

Airway Epithelial Cells ◽

Proximal Region ◽

Transferase Activity ◽

Transcriptional Elongation ◽

Elongation Complex ◽

Histone H3 Acetylation ◽

H3 Acetylation

SummaryRegulation of RNA Polymerase II (Pol2) elongation in the promoter proximal region is an important and ubiquitous control point for gene expression in metazoan cells. We report that transcription of the adenovirus 5 E4 region is regulated during the release of paused Pol2 into productive elongation by recruitment of the super elongation complex (SEC), dependent on promoter H3K18/27 acetylation by CBP/p300. We also establish that this is a general transcriptional regulatory mechanism for ∼6% of genes expressed with FPKM>1 in primary human airway epithelial cells. We observed that a homeostatic mechanism maintains promoter, but not enhancer H3K18/27ac in response to extensive inhibition of CBP/p300 acetyl transferase activity by the highly specific small molecule inhibitor A-485. Further, our results suggest a function for BRD4 association at enhancers in regulating paused Pol2 release at nearby promoters. Taken together, our results uncover processes regulating transcriptional elongation by promoter region histone H3 acetylation and homeostatic maintenance of promoter, but not enhancer, H3K18/27ac in response to inhibition of CBP/p300 acetyl transferase activity.

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CXCL8 histone H3 acetylation is dysfunctional in airway smooth muscle in asthma: regulation by BET

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00021.2015 ◽

2015 ◽

Vol 308 (9) ◽

pp. L962-L972 ◽

Cited By ~ 27

Author(s):

Rachel L. Clifford ◽

Jamie K. Patel ◽

Alison E. John ◽

Amanda L. Tatler ◽

Lisa Mazengarb ◽

...

Keyword(s):

Smooth Muscle ◽

Airway Inflammation ◽

Rna Polymerase Ii ◽

Airway Smooth Muscle ◽

Histone H3 ◽

Steroid Resistant ◽

Cxcl8 Secretion ◽

Promoter Complex ◽

Histone H3 Acetylation ◽

H3 Acetylation

Asthma is characterized by airway inflammation and remodeling and CXCL8 is a CXC chemokine that drives steroid-resistant neutrophilic airway inflammation. We have shown that airway smooth muscle (ASM) cells isolated from asthmatic individuals secrete more CXCL8 than cells from nonasthmatic individuals. Here we investigated chromatin modifications at the CXCL8 promoter in ASM cells from nonasthmatic and asthmatic donors to further understand how CXCL8 is dysregulated in asthma. ASM cells from asthmatic donors had increased histone H3 acetylation, specifically histone H3K18 acetylation, and increased binding of histone acetyltransferase p300 compared with nonasthmatic donors but no differences in CXCL8 DNA methylation. The acetylation reader proteins Brd3 and Brd4 were bound to the CXCL8 promoter and Brd inhibitors inhibited CXCL8 secretion from ASM cells by disrupting Brd4 and RNA polymerase II binding to the CXCL8 promoter. Our results show a novel dysregulation of CXCL8 transcriptional regulation in asthma characterized by a promoter complex that is abnormal in ASM cells isolated from asthmatic donors and can be modulated by Brd inhibitors. Brd inhibitors may provide a new therapeutic strategy for steroid-resistant inflammation.

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Diet-induced epigenetic regulation in vivo of the intestinal fructose transporter Glut5 during development of rat small intestine

Biochemical Journal ◽

10.1042/bj20101987 ◽

2011 ◽

Vol 435 (1) ◽

pp. 43-53 ◽

Cited By ~ 38

Author(s):

Takuji Suzuki ◽

Veronique Douard ◽

Kazuki Mochizuki ◽

Toshinao Goda ◽

Ronaldo P. Ferraris

Keyword(s):

Rna Polymerase Ii ◽

Glucose Transporter ◽

Histone H3 ◽

Solute Carrier Family ◽

Metabolic Complications ◽

Pol Ii ◽

Histone H4 Acetylation ◽

Histone H3 Acetylation ◽

Solute Carrier ◽

H3 Acetylation

Metabolic complications arising from excessive fructose consumption are increasing dramatically even in young children, but little is known about ontogenetic mechanisms regulating Glut5 [glucose transporter 5; encoded by the Slc2a5 (solute carrier family 2 member 5) gene]. Glut5 expression is low postnatally and does not increase, unless luminal fructose and systemic glucocorticoids are present, until ≥14 days of age, suggesting substrate-inducible age- and hormone-sensitive regulation. In the present study, we perfused intestines of 10- and 20-day-old rats with either fructose or glucose then analysed the binding of Pol II (RNA polymerase II) and GR (glucocorticoid receptor), as well as acetylation of histones H3 and H4 by chromatin immunoprecipitation. Abundance of Glut5 mRNA increased only with fructose perfusion and age, a pattern that matched that of Pol II binding and histone H3 acetylation to the Glut5 promoter. Although many regions of the Glut5 promoter respond to developmental signals, fewer regions perceive dietary signals. Age- but not fructose-dependent expression of Sglt1 [sodium-dependent glucose co-transporter 1 encoded by the Slc5a1(solute carrier family 5 member 1) gene] also correlated with Pol II binding and histone H3 acetylation. In contrast, G6Pase (glucose-6-phosphatase; encoded by the G6pc gene) expression, which decreases with age and increases with fructose, is associated only with age-dependent changes in histone H4 acetylation. Induction of Glut5 during ontogenetic development appears to be specifically mediated by GR translocation to the nucleus and subsequent binding to the Glut5 promoter, whereas the glucocorticoid-independent regulation of Sglt1 by age was not associated with any GR binding to the Sglt1 promoter.

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