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Characterization of age signatures of DNA methylation in normal and cancer tissues from multiple studies.

Kim J, Kim K, Kim H, Yoon G, Lee K - BMC Genomics (2014)

Bottom Line: Genes related to the normal signature were enriched for aging-related gene ontology terms including metabolic processes, immune system processes, and cell proliferation.The related gene products of the normal signature had more than the average number of interacting partners in a protein interaction network and had a tendency not to interact directly with each other.The genomic sequences of the normal signature were well conserved and the age-associated DNAm levels could satisfactorily predict the chronological ages of tissues regardless of tissue type.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Informatics, Ajou University School of Medicine, Suwon 443-380, South Korea. kiylee@ajou.ac.kr.

ABSTRACT

Background: DNA methylation (DNAm) levels can be used to predict the chronological age of tissues; however, the characteristics of DNAm age signatures in normal and cancer tissues are not well studied using multiple studies.

Results: We studied approximately 4000 normal and cancer samples with multiple tissue types from diverse studies, and using linear and nonlinear regression models identified reliable tissue type-invariant DNAm age signatures. A normal signature comprising 127 CpG loci was highly enriched on the X chromosome. Age-hypermethylated loci were enriched for guanine-and-cytosine-rich regions in CpG islands (CGIs), whereas age-hypomethylated loci were enriched for adenine-and-thymine-rich regions in non-CGIs. However, the cancer signature comprised only 26 age-hypomethylated loci, none on the X chromosome, and with no overlap with the normal signature. Genes related to the normal signature were enriched for aging-related gene ontology terms including metabolic processes, immune system processes, and cell proliferation. The related gene products of the normal signature had more than the average number of interacting partners in a protein interaction network and had a tendency not to interact directly with each other. The genomic sequences of the normal signature were well conserved and the age-associated DNAm levels could satisfactorily predict the chronological ages of tissues regardless of tissue type. Interestingly, the age-associated DNAm increases or decreases of the normal signature were aberrantly accelerated in cancer samples.

Conclusion: These tissue type-invariant DNAm age signatures in normal and cancer can be used to address important questions in developmental biology and cancer research.

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Related in: MedlinePlus

Disruption of age-associated DNA methylation signature in cancer. (A D) Plots of DNA methylation patterns of normal age-associated loci affiliated with DIRAS3 (CG13697378, CG09118625, and CG24871743 in A), MBD4 (CG19235307 and CG18303397 in B), MYF5 (CG26207503 and CG21126707 in C), and PRR34 (CG26394940 and CG13269407 in D) in normal (blue) and cancer (red) samples. Blue or red lines are the linear (or nonlinear) regression results for normal or cancer samples, respectively. (E) Plots of DNA methylation patterns of tumor suppressor genes including SEMA3B, RRP22 and CDKN2B.
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Fig6: Disruption of age-associated DNA methylation signature in cancer. (A D) Plots of DNA methylation patterns of normal age-associated loci affiliated with DIRAS3 (CG13697378, CG09118625, and CG24871743 in A), MBD4 (CG19235307 and CG18303397 in B), MYF5 (CG26207503 and CG21126707 in C), and PRR34 (CG26394940 and CG13269407 in D) in normal (blue) and cancer (red) samples. Blue or red lines are the linear (or nonlinear) regression results for normal or cancer samples, respectively. (E) Plots of DNA methylation patterns of tumor suppressor genes including SEMA3B, RRP22 and CDKN2B.

Mentions: For several of the 127 normal age-associated DNAm loci, multiple CpG sites were identified in a single gene. For example, CG13697378 (68285433 on chr1), CG09118625 (68285559 on chr1) and CG24871743 (68285238 on chr1) are located in the DIRAS family, GTP-binding RAS-like 3 (DIRAS3) gene. DIRAS3 is known as a tumor-suppressor gene that is expressed in normal ovarian or breast epithelial cells, but is rarely expressed in tumors [26]. These three loci are in CGI regions that show a positive correlation between DNAm levels and age (R = 0.57, 0.62, or 0.67, respectively) in normal tissues (Figure 6A). In cancer, however, no correlation with age that observed and methylation levels were generally high regardless of age. Interestingly, the age-associated DNAm increases or decreases of the normal signature were aberrantly accelerated in cancer samples, indicating that abnormal acceleration in age-associated DNAm change might induce tumorigenesis. In another example, CG19235307 (130642844 on chr3) and CG18303397 (130642825 on chr3), which are in non-CGI regions, are situated in MBD4, methyl-CpG-binding domain protein 4, which is associated with histone-modifying and chromatin-remodeling complexes [27]. These two loci showed a negative correlation between DNAm levels and age in normal tissues. However, the correlation with age disappeared in cancer samples and the DNAm levels of the loci were aberrantly lower (Figure 6B). Similar phenomena were also observed in the multiple age-associated CpG loci in MYF5 (myogenic factor 5) (Figure 6C) and PRR34 (Figure 6D).Figure 6


Characterization of age signatures of DNA methylation in normal and cancer tissues from multiple studies.

Kim J, Kim K, Kim H, Yoon G, Lee K - BMC Genomics (2014)

Disruption of age-associated DNA methylation signature in cancer. (A D) Plots of DNA methylation patterns of normal age-associated loci affiliated with DIRAS3 (CG13697378, CG09118625, and CG24871743 in A), MBD4 (CG19235307 and CG18303397 in B), MYF5 (CG26207503 and CG21126707 in C), and PRR34 (CG26394940 and CG13269407 in D) in normal (blue) and cancer (red) samples. Blue or red lines are the linear (or nonlinear) regression results for normal or cancer samples, respectively. (E) Plots of DNA methylation patterns of tumor suppressor genes including SEMA3B, RRP22 and CDKN2B.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4289351&req=5

Fig6: Disruption of age-associated DNA methylation signature in cancer. (A D) Plots of DNA methylation patterns of normal age-associated loci affiliated with DIRAS3 (CG13697378, CG09118625, and CG24871743 in A), MBD4 (CG19235307 and CG18303397 in B), MYF5 (CG26207503 and CG21126707 in C), and PRR34 (CG26394940 and CG13269407 in D) in normal (blue) and cancer (red) samples. Blue or red lines are the linear (or nonlinear) regression results for normal or cancer samples, respectively. (E) Plots of DNA methylation patterns of tumor suppressor genes including SEMA3B, RRP22 and CDKN2B.
Mentions: For several of the 127 normal age-associated DNAm loci, multiple CpG sites were identified in a single gene. For example, CG13697378 (68285433 on chr1), CG09118625 (68285559 on chr1) and CG24871743 (68285238 on chr1) are located in the DIRAS family, GTP-binding RAS-like 3 (DIRAS3) gene. DIRAS3 is known as a tumor-suppressor gene that is expressed in normal ovarian or breast epithelial cells, but is rarely expressed in tumors [26]. These three loci are in CGI regions that show a positive correlation between DNAm levels and age (R = 0.57, 0.62, or 0.67, respectively) in normal tissues (Figure 6A). In cancer, however, no correlation with age that observed and methylation levels were generally high regardless of age. Interestingly, the age-associated DNAm increases or decreases of the normal signature were aberrantly accelerated in cancer samples, indicating that abnormal acceleration in age-associated DNAm change might induce tumorigenesis. In another example, CG19235307 (130642844 on chr3) and CG18303397 (130642825 on chr3), which are in non-CGI regions, are situated in MBD4, methyl-CpG-binding domain protein 4, which is associated with histone-modifying and chromatin-remodeling complexes [27]. These two loci showed a negative correlation between DNAm levels and age in normal tissues. However, the correlation with age disappeared in cancer samples and the DNAm levels of the loci were aberrantly lower (Figure 6B). Similar phenomena were also observed in the multiple age-associated CpG loci in MYF5 (myogenic factor 5) (Figure 6C) and PRR34 (Figure 6D).Figure 6

Bottom Line: Genes related to the normal signature were enriched for aging-related gene ontology terms including metabolic processes, immune system processes, and cell proliferation.The related gene products of the normal signature had more than the average number of interacting partners in a protein interaction network and had a tendency not to interact directly with each other.The genomic sequences of the normal signature were well conserved and the age-associated DNAm levels could satisfactorily predict the chronological ages of tissues regardless of tissue type.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Informatics, Ajou University School of Medicine, Suwon 443-380, South Korea. kiylee@ajou.ac.kr.

ABSTRACT

Background: DNA methylation (DNAm) levels can be used to predict the chronological age of tissues; however, the characteristics of DNAm age signatures in normal and cancer tissues are not well studied using multiple studies.

Results: We studied approximately 4000 normal and cancer samples with multiple tissue types from diverse studies, and using linear and nonlinear regression models identified reliable tissue type-invariant DNAm age signatures. A normal signature comprising 127 CpG loci was highly enriched on the X chromosome. Age-hypermethylated loci were enriched for guanine-and-cytosine-rich regions in CpG islands (CGIs), whereas age-hypomethylated loci were enriched for adenine-and-thymine-rich regions in non-CGIs. However, the cancer signature comprised only 26 age-hypomethylated loci, none on the X chromosome, and with no overlap with the normal signature. Genes related to the normal signature were enriched for aging-related gene ontology terms including metabolic processes, immune system processes, and cell proliferation. The related gene products of the normal signature had more than the average number of interacting partners in a protein interaction network and had a tendency not to interact directly with each other. The genomic sequences of the normal signature were well conserved and the age-associated DNAm levels could satisfactorily predict the chronological ages of tissues regardless of tissue type. Interestingly, the age-associated DNAm increases or decreases of the normal signature were aberrantly accelerated in cancer samples.

Conclusion: These tissue type-invariant DNAm age signatures in normal and cancer can be used to address important questions in developmental biology and cancer research.

Show MeSH
Related in: MedlinePlus