title: Genome-wide profiling reveals epigenetic inactivation of the PU.1 pathway by histone H3 lysine 27 trimethylation in cytogenetically normal myelodysplastic syndrome.
abstract: Cytogenetically normal myelodysplastic syndrome (CN-MDS) can pose diagnostic challenges and its pathogenetic mechanism remains elusive. By focusing on cytogenetically normal refractory cytopenia with multilineage dysplasia (CN-RCMD), a subtype of MDS, our genome-wide profiling showed ∼4600 annotated gene promoters with increased Histone H3 lysine 27 trimethylation (H3K27me3) in CN-RCMD, when compared with normal controls. Computational analysis revealed a statistically significant enrichment of the PU.1-binding DNA motif (PU-box) in the regions with increased H3K27me3. An inverse relationship between the levels of H3K27me3 and the levels of PU.1 binding and its downstream myeloid gene expressions was observed. Whole-exome sequencing analysis and Sanger sequencing analysis revealed some recurrent mutations, but no mutations in the PU.1 regulatory regions or in the EZH1/2, H3K27 methytransferase encoding genes. Using an MDS-derived erythroid/myeloid line and primary MDS bone marrow cells, we demonstrated that H3K27me3 inhibitors can increase the expression of PU.1 and its downstream genes and also promote cell differentiation via reducing H3K27me3 at the PU.1 gene locus. Finally, ectopic expression of PU.1 significantly inhibited proliferation of the MDS-derived cell line. Based on these data, we propose a hypothetical model of epigenetic inactivation of the PU.1 pathway due to increased H3K27me3 in some cases of CN-RCMD.
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. jasonche@med.umich.edu
authors: J X
authors: JX
authors: Cheng
authors: J
authors: J
authors: Anastasi
authors: K
authors: K
authors: Watanabe
authors: E L
authors: EL
authors: Kleinbrink
authors: E
authors: E
authors: Grimley
authors: R
authors: R
authors: Knibbs
authors: Q J
authors: QJ
authors: Shen
authors: J W
authors: JW
authors: Vardiman
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic; D005260:Female; D005434:Flow Cytometry; D015894:Genome, Human; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008297:Male; D008745:Methylation; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D006657:Histones; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1