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: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Public Library of Science
2012
|
| _version_ | 1826303274905501696 |
|---|---|
| author | Akalin, A Garrett-Bakelman, F Kormaksson, M Busuttil, J Zhang, L Khrebtukova, I Milne, T Huang, Y Biswas, D Hess, J Allis, C Roeder, R Valk, P Löwenberg, B Delwel, R Fernandez, H Paietta, E Tallman, MS Schroth, G Mason, C Melnick, A Figueroa, M |
| author_facet | Akalin, A Garrett-Bakelman, F Kormaksson, M Busuttil, J Zhang, L Khrebtukova, I Milne, T Huang, Y Biswas, D Hess, J Allis, C Roeder, R Valk, P Löwenberg, B Delwel, R Fernandez, H Paietta, E Tallman, MS Schroth, G Mason, C Melnick, A Figueroa, M |
| author_sort | Akalin, A |
| collection | OXFORD |
| 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 | 2024-03-07T06:00:10Z |
| format | Journal article |
| id | oxford-uuid:ebe6f163-9817-4a5e-b46a-1639545e9269 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:00:10Z |
| publishDate | 2012 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:ebe6f163-9817-4a5e-b46a-1639545e92692022-03-27T11:13:35ZBase-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemiaJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ebe6f163-9817-4a5e-b46a-1639545e9269EnglishSymplectic Elements at OxfordPublic Library of Science2012Akalin, AGarrett-Bakelman, FKormaksson, MBusuttil, JZhang, LKhrebtukova, IMilne, THuang, YBiswas, DHess, JAllis, CRoeder, RValk, PLöwenberg, BDelwel, RFernandez, HPaietta, ETallman, MSSchroth, GMason, CMelnick, AFigueroa, MWe 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. |
| spellingShingle | Akalin, A Garrett-Bakelman, F Kormaksson, M Busuttil, J Zhang, L Khrebtukova, I Milne, T Huang, Y Biswas, D Hess, J Allis, C Roeder, R Valk, P Löwenberg, B Delwel, R Fernandez, H Paietta, E Tallman, MS Schroth, G Mason, C Melnick, A Figueroa, M Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia |
| 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 |
| work_keys_str_mv | AT akalina basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT garrettbakelmanf basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT kormakssonm basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT busuttilj basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT zhangl basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT khrebtukovai basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT milnet basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT huangy basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT biswasd basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT hessj basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT allisc basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT roederr basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT valkp basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT lowenbergb basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT delwelr basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT fernandezh basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT paiettae basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT tallmanms basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT schrothg basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT masonc basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT melnicka basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia AT figueroam basepairresolutiondnamethylationsequencingrevealsprofoundlydivergentepigeneticlandscapesinacutemyeloidleukemia |