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Genome-wide quantitative assessment of variation in DNA methylation patterns.

Xie H, Wang M, de Andrade A, Bonaldo Mde F, Galat V, Arndt K, Rajaram V, Goldman S, Tomita T, Soares MB - Nucleic Acids Res. (2011)

Bottom Line: However, little is known about genome-wide variation of DNA methylation patterns.We further identified 12 putative allelic-specific methylated genomic loci, including four Alu elements and eight promoters.Lastly, using subcloned normal fibroblast cells, we demonstrated the highly variable methylation patterns are resulted from low fidelity of DNA methylation inheritance.

View Article: PubMed Central - PubMed

Affiliation: Falk Brain Tumor Center, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago IL 60614-3394, USA. hxie@childrensmemorial.org

ABSTRACT
Genomic DNA methylation contributes substantively to transcriptional regulations that underlie mammalian development and cellular differentiation. Much effort has been made to decipher the molecular mechanisms governing the establishment and maintenance of DNA methylation patterns. However, little is known about genome-wide variation of DNA methylation patterns. In this study, we introduced the concept of methylation entropy, a measure of the randomness of DNA methylation patterns in a cell population, and exploited it to assess the variability in DNA methylation patterns of Alu repeats and promoters. A few interesting observations were made: (i) within a cell population, methylation entropy varies among genomic loci; (ii) among cell populations, the methylation entropies of most genomic loci remain constant; (iii) compared to normal tissue controls, some tumors exhibit greater methylation entropies; (iv) Alu elements with high methylation entropy are associated with high GC content but depletion of CpG dinucleotides and (v) Alu elements in the intronic regions or far from CpG islands are associated with low methylation entropy. We further identified 12 putative allelic-specific methylated genomic loci, including four Alu elements and eight promoters. Lastly, using subcloned normal fibroblast cells, we demonstrated the highly variable methylation patterns are resulted from low fidelity of DNA methylation inheritance.

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Related in: MedlinePlus

The distribution of methylation entropies in tissue samples. The x-axis represents different levels of methylation entropies. The y-axis represents the percentage of genomic loci examined. (A) The distribution of Alu methylation entropies. NC, PN, PA and RL represent normal control, primary non-aggressive, primary aggressive and relapsed ependymoma tissues, respectively. PA1* and RL1* were derived from one same individual. (B) The distribution of methylation entropies of all possible segments with six contiguous CpG sites in promoters and CGIs on chromosome 21.
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Figure 3: The distribution of methylation entropies in tissue samples. The x-axis represents different levels of methylation entropies. The y-axis represents the percentage of genomic loci examined. (A) The distribution of Alu methylation entropies. NC, PN, PA and RL represent normal control, primary non-aggressive, primary aggressive and relapsed ependymoma tissues, respectively. PA1* and RL1* were derived from one same individual. (B) The distribution of methylation entropies of all possible segments with six contiguous CpG sites in promoters and CGIs on chromosome 21.

Mentions: The distribution of methylation entropies was determined for each sample. Within a cell population, the methylation entropy varied among different genomic loci. Approximately 5–10% of genomic loci in each sample exhibited zero methylation entropy, which indicated that only one methylation pattern was found in sixteen or more sequence-reads (Figure 3A). Since Alu repeats are heavily methylated in the genome, the average methylation level for the two data sets was found to be >90% (21,22). Therefore, the majority of the genomic loci that exhibited zero methylation entropy were completely methylated. Such uniformity in the pattern of DNA methylation suggests that these genomic regions exhibit extremely high fidelity of inheritance of DNA methylation. Three out of eight tissues samples, including two normal controls and one primary non-aggressive ependymoma, had a very similar distribution of methylation entropies. Shifts to higher methylation entropies were observed in the remainder ependymomas (Figure 3A). This suggests that tumors, especially those that are most aggressive, might be characterized by an increased genome-wide disorder in DNA methylation patterns.Figure 3.


Genome-wide quantitative assessment of variation in DNA methylation patterns.

Xie H, Wang M, de Andrade A, Bonaldo Mde F, Galat V, Arndt K, Rajaram V, Goldman S, Tomita T, Soares MB - Nucleic Acids Res. (2011)

The distribution of methylation entropies in tissue samples. The x-axis represents different levels of methylation entropies. The y-axis represents the percentage of genomic loci examined. (A) The distribution of Alu methylation entropies. NC, PN, PA and RL represent normal control, primary non-aggressive, primary aggressive and relapsed ependymoma tissues, respectively. PA1* and RL1* were derived from one same individual. (B) The distribution of methylation entropies of all possible segments with six contiguous CpG sites in promoters and CGIs on chromosome 21.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3105398&req=5

Figure 3: The distribution of methylation entropies in tissue samples. The x-axis represents different levels of methylation entropies. The y-axis represents the percentage of genomic loci examined. (A) The distribution of Alu methylation entropies. NC, PN, PA and RL represent normal control, primary non-aggressive, primary aggressive and relapsed ependymoma tissues, respectively. PA1* and RL1* were derived from one same individual. (B) The distribution of methylation entropies of all possible segments with six contiguous CpG sites in promoters and CGIs on chromosome 21.
Mentions: The distribution of methylation entropies was determined for each sample. Within a cell population, the methylation entropy varied among different genomic loci. Approximately 5–10% of genomic loci in each sample exhibited zero methylation entropy, which indicated that only one methylation pattern was found in sixteen or more sequence-reads (Figure 3A). Since Alu repeats are heavily methylated in the genome, the average methylation level for the two data sets was found to be >90% (21,22). Therefore, the majority of the genomic loci that exhibited zero methylation entropy were completely methylated. Such uniformity in the pattern of DNA methylation suggests that these genomic regions exhibit extremely high fidelity of inheritance of DNA methylation. Three out of eight tissues samples, including two normal controls and one primary non-aggressive ependymoma, had a very similar distribution of methylation entropies. Shifts to higher methylation entropies were observed in the remainder ependymomas (Figure 3A). This suggests that tumors, especially those that are most aggressive, might be characterized by an increased genome-wide disorder in DNA methylation patterns.Figure 3.

Bottom Line: However, little is known about genome-wide variation of DNA methylation patterns.We further identified 12 putative allelic-specific methylated genomic loci, including four Alu elements and eight promoters.Lastly, using subcloned normal fibroblast cells, we demonstrated the highly variable methylation patterns are resulted from low fidelity of DNA methylation inheritance.

View Article: PubMed Central - PubMed

Affiliation: Falk Brain Tumor Center, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago IL 60614-3394, USA. hxie@childrensmemorial.org

ABSTRACT
Genomic DNA methylation contributes substantively to transcriptional regulations that underlie mammalian development and cellular differentiation. Much effort has been made to decipher the molecular mechanisms governing the establishment and maintenance of DNA methylation patterns. However, little is known about genome-wide variation of DNA methylation patterns. In this study, we introduced the concept of methylation entropy, a measure of the randomness of DNA methylation patterns in a cell population, and exploited it to assess the variability in DNA methylation patterns of Alu repeats and promoters. A few interesting observations were made: (i) within a cell population, methylation entropy varies among genomic loci; (ii) among cell populations, the methylation entropies of most genomic loci remain constant; (iii) compared to normal tissue controls, some tumors exhibit greater methylation entropies; (iv) Alu elements with high methylation entropy are associated with high GC content but depletion of CpG dinucleotides and (v) Alu elements in the intronic regions or far from CpG islands are associated with low methylation entropy. We further identified 12 putative allelic-specific methylated genomic loci, including four Alu elements and eight promoters. Lastly, using subcloned normal fibroblast cells, we demonstrated the highly variable methylation patterns are resulted from low fidelity of DNA methylation inheritance.

Show MeSH
Related in: MedlinePlus