Epigenetic changes in myelofibrosis: Distinct methylation changes in the myeloid compartments and in cases with ASXL1 mutations

Helene Myrtue Nielsen; Christen Lykkegaard Andersen; Maj Westman; Lasse Sommer Kristensen; Fazila Asmar; Torben Arvid Kruse; Mads Thomassen; Thomas Stauffer Larsen; Vibe Skov; Lise Lotte Hansen; Ole Weis Bjerrum; Hans Carl Hasselbalch; Vasu Punj; Kirsten Grønbæk

doi:10.1038/s41598-017-07057-3

Epigenetic changes in myelofibrosis: Distinct methylation changes in the myeloid compartments and in cases with ASXL1 mutations

Helene Myrtue Nielsen, Christen Lykkegaard Andersen, Maj Westman, Lasse Sommer Kristensen, Fazila Asmar, Torben Arvid Kruse, Mads Thomassen, Thomas Stauffer Larsen, Vibe Skov, Lise Lotte Hansen, Ole Weis Bjerrum, Hans Carl Hasselbalch, Vasu Punj, Kirsten Grønbæk

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Abstract

This is the first study to compare genome-wide DNA methylation profiles of sorted blood cells from myelofibrosis (MF) patients and healthy controls. We found that differentially methylated CpG sites located to genes involved in 'cancer' and 'embryonic development' in MF CD34+ cells, in 'inflammatory disease' in MF mononuclear cells, and in 'immunological diseases' in MF granulocytes. Only few differentially methylated CpG sites were common among the three cell populations. Mutations in the epigenetic regulators ASXL1 (47%) and TET2 (20%) were not associated with a specific DNA methylation pattern using an unsupervised approach. However, in a supervised analysis of ASXL1 mutated versus wild-type cases, differentially methylated CpG sites were enriched in regions marked by histone H3K4me1, histone H3K27me3, and the bivalent histone mark H3K27me3 + H3K4me3 in human CD34+ cells. Hypermethylation of selected CpG sites was confirmed in a separate validation cohort of 30 MF patients by pyrosequencing. Altogether, we show that individual MF cell populations have distinct differentially methylated genes relative to their normal counterparts, which likely contribute to the phenotypic characteristics of MF. Furthermore, differentially methylated CpG sites in ASXL1 mutated MF cases are found in regulatory regions that could be associated with aberrant gene expression of ASXL1 target genes.

Original language	English
Article number	6774
Journal	Scientific Reports
Volume	7
Number of pages	11
ISSN	2045-2322
DOIs	https://doi.org/10.1038/s41598-017-07057-3
Publication status	Published - 1 Dec 2017

Keywords

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41598-017-07057-3Licence: CC BY

Epigenetic changes in myelofbrosis: Distinct methylation changes in the myeloid compartments and in cases with ASXL1 mutationsFinal published version, 1.64 MBLicence: CC BY

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Myrtue Nielsen, H., Lykkegaard Andersen, C., Westman, M., Sommer Kristensen, L., Asmar, F., Arvid Kruse, T., Thomassen, M., Stauffer Larsen, T., Skov, V., Lotte Hansen, L., Weis Bjerrum, O., Hasselbalch, H. C., Punj, V., & Grønbæk, K. (2017). Epigenetic changes in myelofibrosis: Distinct methylation changes in the myeloid compartments and in cases with ASXL1 mutations. Scientific Reports, 7, Article 6774. https://doi.org/10.1038/s41598-017-07057-3

Myrtue Nielsen, H, Lykkegaard Andersen, C, Westman, M, Sommer Kristensen, L, Asmar, F, Arvid Kruse, T, Thomassen, M, Stauffer Larsen, T, Skov, V, Lotte Hansen, L, Weis Bjerrum, O, Hasselbalch, HC, Punj, V & Grønbæk, K 2017, 'Epigenetic changes in myelofibrosis: Distinct methylation changes in the myeloid compartments and in cases with ASXL1 mutations', Scientific Reports, vol. 7, 6774. https://doi.org/10.1038/s41598-017-07057-3

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abstract = "This is the first study to compare genome-wide DNA methylation profiles of sorted blood cells from myelofibrosis (MF) patients and healthy controls. We found that differentially methylated CpG sites located to genes involved in 'cancer' and 'embryonic development' in MF CD34+ cells, in 'inflammatory disease' in MF mononuclear cells, and in 'immunological diseases' in MF granulocytes. Only few differentially methylated CpG sites were common among the three cell populations. Mutations in the epigenetic regulators ASXL1 (47%) and TET2 (20%) were not associated with a specific DNA methylation pattern using an unsupervised approach. However, in a supervised analysis of ASXL1 mutated versus wild-type cases, differentially methylated CpG sites were enriched in regions marked by histone H3K4me1, histone H3K27me3, and the bivalent histone mark H3K27me3 + H3K4me3 in human CD34+ cells. Hypermethylation of selected CpG sites was confirmed in a separate validation cohort of 30 MF patients by pyrosequencing. Altogether, we show that individual MF cell populations have distinct differentially methylated genes relative to their normal counterparts, which likely contribute to the phenotypic characteristics of MF. Furthermore, differentially methylated CpG sites in ASXL1 mutated MF cases are found in regulatory regions that could be associated with aberrant gene expression of ASXL1 target genes.",

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AU - Myrtue Nielsen, Helene

AU - Lykkegaard Andersen, Christen

AU - Westman, Maj

AU - Sommer Kristensen, Lasse

AU - Asmar, Fazila

AU - Arvid Kruse, Torben

AU - Thomassen, Mads

AU - Stauffer Larsen, Thomas

AU - Skov, Vibe

AU - Lotte Hansen, Lise

AU - Weis Bjerrum, Ole

AU - Hasselbalch, Hans Carl

AU - Punj, Vasu

AU - Grønbæk, Kirsten

PY - 2017/12/1

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N2 - This is the first study to compare genome-wide DNA methylation profiles of sorted blood cells from myelofibrosis (MF) patients and healthy controls. We found that differentially methylated CpG sites located to genes involved in 'cancer' and 'embryonic development' in MF CD34+ cells, in 'inflammatory disease' in MF mononuclear cells, and in 'immunological diseases' in MF granulocytes. Only few differentially methylated CpG sites were common among the three cell populations. Mutations in the epigenetic regulators ASXL1 (47%) and TET2 (20%) were not associated with a specific DNA methylation pattern using an unsupervised approach. However, in a supervised analysis of ASXL1 mutated versus wild-type cases, differentially methylated CpG sites were enriched in regions marked by histone H3K4me1, histone H3K27me3, and the bivalent histone mark H3K27me3 + H3K4me3 in human CD34+ cells. Hypermethylation of selected CpG sites was confirmed in a separate validation cohort of 30 MF patients by pyrosequencing. Altogether, we show that individual MF cell populations have distinct differentially methylated genes relative to their normal counterparts, which likely contribute to the phenotypic characteristics of MF. Furthermore, differentially methylated CpG sites in ASXL1 mutated MF cases are found in regulatory regions that could be associated with aberrant gene expression of ASXL1 target genes.

AB - This is the first study to compare genome-wide DNA methylation profiles of sorted blood cells from myelofibrosis (MF) patients and healthy controls. We found that differentially methylated CpG sites located to genes involved in 'cancer' and 'embryonic development' in MF CD34+ cells, in 'inflammatory disease' in MF mononuclear cells, and in 'immunological diseases' in MF granulocytes. Only few differentially methylated CpG sites were common among the three cell populations. Mutations in the epigenetic regulators ASXL1 (47%) and TET2 (20%) were not associated with a specific DNA methylation pattern using an unsupervised approach. However, in a supervised analysis of ASXL1 mutated versus wild-type cases, differentially methylated CpG sites were enriched in regions marked by histone H3K4me1, histone H3K27me3, and the bivalent histone mark H3K27me3 + H3K4me3 in human CD34+ cells. Hypermethylation of selected CpG sites was confirmed in a separate validation cohort of 30 MF patients by pyrosequencing. Altogether, we show that individual MF cell populations have distinct differentially methylated genes relative to their normal counterparts, which likely contribute to the phenotypic characteristics of MF. Furthermore, differentially methylated CpG sites in ASXL1 mutated MF cases are found in regulatory regions that could be associated with aberrant gene expression of ASXL1 target genes.

KW - Journal Article

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DO - 10.1038/s41598-017-07057-3

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JO - Scientific Reports

JF - Scientific Reports

M1 - 6774

ER -

Epigenetic changes in myelofibrosis: Distinct methylation changes in the myeloid compartments and in cases with ASXL1 mutations

Abstract

Keywords

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