TY - JOUR
T1 - Epigenetic changes in myelofibrosis
T2 - Distinct methylation changes in the myeloid compartments and in cases with ASXL1 mutations
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
Y1 - 2017/12/1
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
U2 - 10.1038/s41598-017-07057-3
DO - 10.1038/s41598-017-07057-3
M3 - Journal article
C2 - 28754985
SN - 2045-2322
VL - 7
JO - Scientific Reports
JF - Scientific Reports
M1 - 6774
ER -
