Limits...
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.

Show MeSH

Related in: MedlinePlus

Network characteristics and sequence conservation of the age-associated DNA methylation signature. (A) Protein interactions of age-associated DNA methylation genes in normal tissue. Blue or green nodes indicate genes hypo- or hypermethylated with age; gray nodes indicate the interacting neighbors of the age-associated gene products. Red or yellow borders of nodes indicate whether the loci are located in CGIs (red) or non-CGIs (purple). Edges between nodes indicate the protein–protein interactions of gene products. Node sizes are proportional to numbers of interacting proteins. (B) The distributions of numbers of interacting protein neighbors from the network shown in (A) (in red), or from all protein interactions combined (in blue), respectively. (C) The number of direct protein interactions between gene products affiliated with the age-associated DNA methylation signature is indicated by a red arrow. The black curve indicates the distribution of 106 random selections of proteins with the same number of the age-associated genes. (D) The number of the age-associated DNA loci with significant the average phyloP scores (>1.3) is indicated by a red arrow. The black curve indicates the background distribution of the human genome. (E) Surrounding sequences of age-associated loci in MYF5 and MYF6.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4289351&req=5

Fig7: Network characteristics and sequence conservation of the age-associated DNA methylation signature. (A) Protein interactions of age-associated DNA methylation genes in normal tissue. Blue or green nodes indicate genes hypo- or hypermethylated with age; gray nodes indicate the interacting neighbors of the age-associated gene products. Red or yellow borders of nodes indicate whether the loci are located in CGIs (red) or non-CGIs (purple). Edges between nodes indicate the protein–protein interactions of gene products. Node sizes are proportional to numbers of interacting proteins. (B) The distributions of numbers of interacting protein neighbors from the network shown in (A) (in red), or from all protein interactions combined (in blue), respectively. (C) The number of direct protein interactions between gene products affiliated with the age-associated DNA methylation signature is indicated by a red arrow. The black curve indicates the distribution of 106 random selections of proteins with the same number of the age-associated genes. (D) The number of the age-associated DNA loci with significant the average phyloP scores (>1.3) is indicated by a red arrow. The black curve indicates the background distribution of the human genome. (E) Surrounding sequences of age-associated loci in MYF5 and MYF6.

Mentions: We examined the human protein interaction network of the 127 normal age-associated loci, mapped to 122 unique genes (Figure 7A). For this human protein interaction network analysis, we integrated protein interactions from a number of open databases (Methods). We found that a protein interaction subnetwork that included the first neighbors of 122 gene products under the integrated network included 1163 proteins and 12,620 interactions between them. Analysis of the number of interacting neighbors revealed that the age-associated gene products in the normal signature had relatively more interacting partners than the average for all proteins in the prepared interaction network, and the overall distributions differed significantly between them (Wilcoxon rank-sum test, P = 0.0043; Figure 7B). Furthermore, the 122 unique gene products tended not to interact directly with each other: only one interaction existed among the 122 gene products (Z test, P = 0.0038; Figure 7C). This indicates that the age-associated gene products cover a large portion of the human protein interaction network. We also analyzed the DNA sequence conservation scores of the 127 CpG positions using the average phyloP [29] (Figure 7D). The results showed that 15 CpG positions (“Conserved CpG” in Additional file 1: Table S2) had significantly higher conservation scores (average phyloP score > 1.3) and that this number was significantly higher than random expectations (P = 3.56E–09 from a Z test using the phyloP distribution of 10,000 random selection tests). Gene ontology term analysis of the highly conserved loci showed that aging-associated terms such as metabolic processes (P = 1.40E–06), muscle system processes (P = 8.68E–05), and cell proliferation (P = 1.87E–02) were enriched (Additional file 1: Table S7). Of highly conserved loci, MYF5 and MYF6 are associated with myogenic regulation, which is related with a decrease of muscle in mass, strength, and contraction in aging [30]. The sequences surrounding MYF5 and MYF6 in CGI are enriched guanine and cytosine nucleotides (Figure 7E).Figure 7


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)

Network characteristics and sequence conservation of the age-associated DNA methylation signature. (A) Protein interactions of age-associated DNA methylation genes in normal tissue. Blue or green nodes indicate genes hypo- or hypermethylated with age; gray nodes indicate the interacting neighbors of the age-associated gene products. Red or yellow borders of nodes indicate whether the loci are located in CGIs (red) or non-CGIs (purple). Edges between nodes indicate the protein–protein interactions of gene products. Node sizes are proportional to numbers of interacting proteins. (B) The distributions of numbers of interacting protein neighbors from the network shown in (A) (in red), or from all protein interactions combined (in blue), respectively. (C) The number of direct protein interactions between gene products affiliated with the age-associated DNA methylation signature is indicated by a red arrow. The black curve indicates the distribution of 106 random selections of proteins with the same number of the age-associated genes. (D) The number of the age-associated DNA loci with significant the average phyloP scores (>1.3) is indicated by a red arrow. The black curve indicates the background distribution of the human genome. (E) Surrounding sequences of age-associated loci in MYF5 and MYF6.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4289351&req=5

Fig7: Network characteristics and sequence conservation of the age-associated DNA methylation signature. (A) Protein interactions of age-associated DNA methylation genes in normal tissue. Blue or green nodes indicate genes hypo- or hypermethylated with age; gray nodes indicate the interacting neighbors of the age-associated gene products. Red or yellow borders of nodes indicate whether the loci are located in CGIs (red) or non-CGIs (purple). Edges between nodes indicate the protein–protein interactions of gene products. Node sizes are proportional to numbers of interacting proteins. (B) The distributions of numbers of interacting protein neighbors from the network shown in (A) (in red), or from all protein interactions combined (in blue), respectively. (C) The number of direct protein interactions between gene products affiliated with the age-associated DNA methylation signature is indicated by a red arrow. The black curve indicates the distribution of 106 random selections of proteins with the same number of the age-associated genes. (D) The number of the age-associated DNA loci with significant the average phyloP scores (>1.3) is indicated by a red arrow. The black curve indicates the background distribution of the human genome. (E) Surrounding sequences of age-associated loci in MYF5 and MYF6.
Mentions: We examined the human protein interaction network of the 127 normal age-associated loci, mapped to 122 unique genes (Figure 7A). For this human protein interaction network analysis, we integrated protein interactions from a number of open databases (Methods). We found that a protein interaction subnetwork that included the first neighbors of 122 gene products under the integrated network included 1163 proteins and 12,620 interactions between them. Analysis of the number of interacting neighbors revealed that the age-associated gene products in the normal signature had relatively more interacting partners than the average for all proteins in the prepared interaction network, and the overall distributions differed significantly between them (Wilcoxon rank-sum test, P = 0.0043; Figure 7B). Furthermore, the 122 unique gene products tended not to interact directly with each other: only one interaction existed among the 122 gene products (Z test, P = 0.0038; Figure 7C). This indicates that the age-associated gene products cover a large portion of the human protein interaction network. We also analyzed the DNA sequence conservation scores of the 127 CpG positions using the average phyloP [29] (Figure 7D). The results showed that 15 CpG positions (“Conserved CpG” in Additional file 1: Table S2) had significantly higher conservation scores (average phyloP score > 1.3) and that this number was significantly higher than random expectations (P = 3.56E–09 from a Z test using the phyloP distribution of 10,000 random selection tests). Gene ontology term analysis of the highly conserved loci showed that aging-associated terms such as metabolic processes (P = 1.40E–06), muscle system processes (P = 8.68E–05), and cell proliferation (P = 1.87E–02) were enriched (Additional file 1: Table S7). Of highly conserved loci, MYF5 and MYF6 are associated with myogenic regulation, which is related with a decrease of muscle in mass, strength, and contraction in aging [30]. The sequences surrounding MYF5 and MYF6 in CGI are enriched guanine and cytosine nucleotides (Figure 7E).Figure 7

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