Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia.
We have developed an enhanced form of reduced representation bisulfite sequencing with extended genomic coverage, which resulted in greater capture of DNA methylation information of regions lying outside of traditional CpG islands. Applying this method to primary human bone marrow specimens from pat...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC3380828?pdf=render |
| _version_ | 1818311547898822656 |
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| author | Altuna Akalin Francine E Garrett-Bakelman Matthias Kormaksson Jennifer Busuttil Lu Zhang Irina Khrebtukova Thomas A Milne Yongsheng Huang Debabrata Biswas Jay L Hess C David Allis Robert G Roeder Peter J M Valk Bob Löwenberg Ruud Delwel Hugo F Fernandez Elisabeth Paietta Martin S Tallman Gary P Schroth Christopher E Mason Ari Melnick Maria E Figueroa |
| author_facet | Altuna Akalin Francine E Garrett-Bakelman Matthias Kormaksson Jennifer Busuttil Lu Zhang Irina Khrebtukova Thomas A Milne Yongsheng Huang Debabrata Biswas Jay L Hess C David Allis Robert G Roeder Peter J M Valk Bob Löwenberg Ruud Delwel Hugo F Fernandez Elisabeth Paietta Martin S Tallman Gary P Schroth Christopher E Mason Ari Melnick Maria E Figueroa |
| author_sort | Altuna Akalin |
| collection | DOAJ |
| description | We have developed an enhanced form of reduced representation bisulfite sequencing with extended genomic coverage, which resulted in greater capture of DNA methylation information of regions lying outside of traditional CpG islands. Applying this method to primary human bone marrow specimens from patients with Acute Myelogeneous Leukemia (AML), we demonstrated that genetically distinct AML subtypes display diametrically opposed DNA methylation patterns. As compared to normal controls, we observed widespread hypermethylation in IDH mutant AMLs, preferentially targeting promoter regions and CpG islands neighboring the transcription start sites of genes. In contrast, AMLs harboring translocations affecting the MLL gene displayed extensive loss of methylation of an almost mutually exclusive set of CpGs, which instead affected introns and distal intergenic CpG islands and shores. When analyzed in conjunction with gene expression profiles, it became apparent that these specific patterns of DNA methylation result in differing roles in gene expression regulation. However, despite this subtype-specific DNA methylation patterning, a much smaller set of CpG sites are consistently affected in both AML subtypes. Most CpG sites in this common core of aberrantly methylated CpGs were hypermethylated in both AML subtypes. Therefore, aberrant DNA methylation patterns in AML do not occur in a stereotypical manner but rather are highly specific and associated with specific driving genetic lesions. |
| first_indexed | 2024-12-13T08:03:42Z |
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| id | doaj.art-cc7e491136c64fee8e206697389fba8c |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-13T08:03:42Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Genetics |
| spelling | doaj.art-cc7e491136c64fee8e206697389fba8c2022-12-21T23:54:21ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042012-01-0186e100278110.1371/journal.pgen.1002781Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia.Altuna AkalinFrancine E Garrett-BakelmanMatthias KormakssonJennifer BusuttilLu ZhangIrina KhrebtukovaThomas A MilneYongsheng HuangDebabrata BiswasJay L HessC David AllisRobert G RoederPeter J M ValkBob LöwenbergRuud DelwelHugo F FernandezElisabeth PaiettaMartin S TallmanGary P SchrothChristopher E MasonAri MelnickMaria E FigueroaWe have developed an enhanced form of reduced representation bisulfite sequencing with extended genomic coverage, which resulted in greater capture of DNA methylation information of regions lying outside of traditional CpG islands. Applying this method to primary human bone marrow specimens from patients with Acute Myelogeneous Leukemia (AML), we demonstrated that genetically distinct AML subtypes display diametrically opposed DNA methylation patterns. As compared to normal controls, we observed widespread hypermethylation in IDH mutant AMLs, preferentially targeting promoter regions and CpG islands neighboring the transcription start sites of genes. In contrast, AMLs harboring translocations affecting the MLL gene displayed extensive loss of methylation of an almost mutually exclusive set of CpGs, which instead affected introns and distal intergenic CpG islands and shores. When analyzed in conjunction with gene expression profiles, it became apparent that these specific patterns of DNA methylation result in differing roles in gene expression regulation. However, despite this subtype-specific DNA methylation patterning, a much smaller set of CpG sites are consistently affected in both AML subtypes. Most CpG sites in this common core of aberrantly methylated CpGs were hypermethylated in both AML subtypes. Therefore, aberrant DNA methylation patterns in AML do not occur in a stereotypical manner but rather are highly specific and associated with specific driving genetic lesions.http://europepmc.org/articles/PMC3380828?pdf=render |
| spellingShingle | Altuna Akalin Francine E Garrett-Bakelman Matthias Kormaksson Jennifer Busuttil Lu Zhang Irina Khrebtukova Thomas A Milne Yongsheng Huang Debabrata Biswas Jay L Hess C David Allis Robert G Roeder Peter J M Valk Bob Löwenberg Ruud Delwel Hugo F Fernandez Elisabeth Paietta Martin S Tallman Gary P Schroth Christopher E Mason Ari Melnick Maria E Figueroa Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia. PLoS Genetics |
| title | Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia. |
| title_full | Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia. |
| title_fullStr | Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia. |
| title_full_unstemmed | Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia. |
| title_short | Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia. |
| title_sort | base pair resolution dna methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia |
| url | http://europepmc.org/articles/PMC3380828?pdf=render |
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