CDKN2B Methylation and Aortic Arch Calcification in Patients with Ischemic Stroke

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Aim: CDKN2A/2B near chromosome 9p21 has been proposed as a potential genetic etiology for both atherosclerosis and arterial calcification. DNA methylation, which can change the expression of CDKN2A/2B, may be an underlying mechanism for this association. This study aimed to evaluate whether CDKN2A/2B methylation is related to aortic arch calcification (AAC) in patients with ischemic stroke.

Methods: DNA methylation levels of CDKN2A/2B was measured using venous blood samples in 322 patients with ischemic stroke. A total of 36 CpG sites around promoter regions of CDKN2A/2B were examined. AAC was quantified with Agatston score based on results of computed tomography angiography.

Results: There were 248 (77.0%) patients with and 74 (23.0%) patients without evident AAC. Compared with patients without AAC, patients with AAC had higher methylation levels of CDKN2B (5.72 vs 4.94, P < 0.001). Using a generalized linear model, positive correlation between methylation levels and log-transformed calcification scores was detected at CDKN2B ( β = 0.275 ± 0.116, P = 0.018).

Conclusion: Patients with higher levels of DNA methylation of CDKN2B may bear increased risk for AAC. Further studies to reveal the underlying mechanisms of this association are warranted for establishing a cause–effect relationship.

Related collections

Most cited references 27

Record: found
Abstract: found
Article: not found

CpG islands in vertebrate genomes.

M. Gardiner-Garden, M Frommer (1987)

Although vertebrate DNA is generally depleted in the dinucleotide CpG, it has recently been shown that some vertebrate genes contain CpG islands, regions of DNA with a high G+C content and a high frequency of CpG dinucleotides relative to the bulk genome. In this study, a large number of sequences of vertebrate genes were screened for the presence of CpG islands. Each CpG island was then analysed in terms of length, nucleotide composition, frequency of CpG dinucleotides, and location relative to the transcription unit of the associated gene. CpG islands were associated with the 5' ends of all housekeeping genes and many tissue-specific genes, and with the 3' ends of some tissue-specific genes. A few genes contained both 5' and 3' CpG islands, separated by several thousand base-pairs of CpG-depleted DNA. The 5' CpG islands extended through 5'-flanking DNA, exons and introns, whereas most of the 3' CpG islands appeared to be associated with exons. CpG islands were generally found in the same position relative to the transcription unit of equivalent genes in different species, with some notable exceptions. The locations of G/C boxes, composed of the sequence GGGCGG or its reverse complement CCGCCC, were investigated relative to the location of CpG islands. G/C boxes were found to be rare in CpG-depleted DNA and plentiful in CpG islands, where they occurred in 3' CpG islands, as well as in 5' CpG islands associated with tissue-specific and housekeeping genes. G/C boxes were located both upstream and downstream from the transcription start site of genes with 5' CpG islands. Thus, G/C boxes appeared to be a feature of CpG islands in general, rather than a feature of the promoter region of housekeeping genes. Two theories for the maintenance of a high frequency of CpG dinucleotides in CpG islands were tested: that CpG islands in methylated genomes are maintained, despite a tendency for 5mCpG to mutate by deamination to TpG+CpA, by the structural stability of a high G+C content alone, and that CpG islands associated with exons result from some selective importance of the arginine codon CGX. Neither of these theories could account for the distribution of CpG dinucleotides in the sequences analysed. Possible functions of CpG islands in transcriptional and post-transcriptional regulation of gene expression were discussed, and were related to theories for the maintenance of CpG islands as "methylation-free zones" in germline DNA.

0 comments Cited 459 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene.

Y Kotake, T. Nakagawa, K Kitagawa … (2011)

A 42 kb region on human chromosome 9p21 encodes for three distinct tumor suppressors, p16(INK4A), p14(ARF) and p15(INK4B), and is altered in an estimated 30-40% of human tumors. The expression of the INK4A-ARF-INK4B gene cluster is silenced by polycomb during normal cell growth and is activated by oncogenic insults and during aging. How the polycomb is recruited to repress this gene cluster is unclear. Here, we show that expression of oncogenic Ras, which stimulates the expression of p15(INK4B) and p16(INK4A), but not p14(ARF), inhibits the expression of ANRIL (antisense non-coding RNA in the INK4 locus), a 3.8 kb-long non-coding RNA expressed in the opposite direction from INK4A-ARF-INK4B. We show that the p15(INK4B) locus is bound by SUZ12, a component of polycomb repression complex 2 (PRC2), and is H3K27-trimethylated. Notably, depletion of ANRIL disrupts the SUZ12 binding to the p15(INK4B) locus, increases the expression of p15(INK4B), but not p16(INK4A) or p14(ARF), and inhibits cellular proliferation. Finally, RNA immunoprecipitation demonstrates that ANRIL binds to SUZ12 in vivo. Collectively, these results suggest a model in which ANRIL binds to and recruits PRC2 to repress the expression of p15(INK4B) locus.

0 comments Cited 399 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future.

Manel Esteller (2002)

We have come a long way since the first reports of the existence of aberrant DNA methylation in human cancer. Hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes is now firmly established as an important mechanism for gene inactivation. CpG island hypermethylation has been described in almost every tumor type. Many cellular pathways are inactivated by this type of epigenetic lesion: DNA repair (hMLH1, MGMT), cell cycle (p16(INK4a), p15(INK4b), p14(ARF)), apoptosis (DAPK), cell adherence (CDH1, CDH13), detoxification (GSTP1), etc em leader However, we still know little of the mechanisms of aberrant methylation and why certain genes are selected over others. Hypermethylation is not an isolated layer of epigenetic control, but is linked to the other pieces of the puzzle such as methyl-binding proteins, DNA methyltransferases and histone deacetylase, but our understanding of the degree of specificity of these epigenetic layers in the silencing of specific tumor suppressor genes remains incomplete. The explosion of user-friendly technologies has given rise to a rapidly increasing list of hypermethylated genes. Careful functional and genetic studies are necessary to determine which hypermethylation events are truly relevant for human tumorigenesis. The development of CpG island hypermethylation profiles for every form of human tumors has yielded valuable pilot clinical data in monitoring and treating cancer patients based in our knowledge of DNA methylation. Basic and translational will both be needed in the near future to fully understand the mechanisms, roles and uses of CpG island hypermethylation in human cancer. The expectations are high.

0 comments Cited 294 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): J Atheroscler Thromb

Journal ID (iso-abbrev): J. Atheroscler. Thromb

Journal ID (publisher-id): jat

Journal ID (hwp): jat

Title: Journal of Atherosclerosis and Thrombosis

Publisher: Japan Atherosclerosis Society

ISSN (Print): 1340-3478

ISSN (Electronic): 1880-3873

Publication date (Print): 1 June 2017

Volume: 24

Issue: 6

Pages: 609-620

Affiliations

[1 ]Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China

[2 ]Department of Gerontology, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China

[3 ]Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, China

[4 ]Department of Neurology, Jinling Hospital, Southern Medical University, Nanjing, China

Author notes

Address for correspondence: Gelin Xu, Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu, China E-mail: gelinxu@ 123456nju.edu.cn

Article

DOI: 10.5551/jat.36897

PMC ID: 5453686

PubMed ID: 27773886

SO-VID: 7fa8ac7b-3ff1-46b2-84a2-1c253c6dd86c

License:

This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License. http://creativecommons.org/licenses/by-nc-sa/3.0/

History

Date received : 26 June 2016

Date accepted : 12 September 2016

Page count

Figures: 0, Tables: 10, References: 36, Pages: 12

Comments

Comment on this article

scite_

Cited by 12

See all cited by

Most referenced authors 585

See all reference authors

CDKN2B Methylation and Aortic Arch Calcification in Patients with Ischemic Stroke

Read this article at

Abstract

Related collections

Stroke MRI

Most cited references 27

CpG islands in vertebrate genomes.

Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene.

CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future.

Author and article information

Journal

Affiliations

Author notes

Article

History

Page count

Categories

Comments

Comment on this article

Similar content 765

Cited by 12

Most referenced authors 585