Cancer-specific changes in DNA methylation reveal aberrant silencing and activation of enhancers in leukemia

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Item Type:	Article
Title:	Cancer-specific changes in DNA methylation reveal aberrant silencing and activation of enhancers in leukemia
Creators Name:	Qu, Y., Siggens, L., Cordeddu, L., Gaidzik, V.I., Karlsson, K., Bullinger, L., Döhner, K., Ekwall, K., Lehmann, S. and Lennartsson, A.
Abstract:	Acute myeloid leukemia (AML) is characterized by an impaired differentiation process leading to an accumulation of immature blasts in the blood. One feature of cytogenetically normal AML is alterations to the DNA methylome. We analyzed 57 AML patients with normal karyotype by using Illumina's 450k array and showed that aberrant DNA methylation is significantly altered at enhancer regions and that the methylation levels at specific enhancers predict overall survival of AML patients. The majority of sites that become differentially methylated in AML occur in regulatory elements of the human genome. Hypermethylation associates with enhancer silencing. In addition, chromatin immunoprecipitation sequencing analyses showed that a subset of hypomethylated sites correlate with enhancer activation, indicated by increased H3K27 acetylation. DNA hypomethylation is therefore not sufficient for enhancer activation. Some sites of hypomethylation occur at weak/poised enhancers marked with H3K4 monomethylation in hematopoietic progenitor cells. Other hypomethylated regions occur at sites inactive in progenitors and reflect the de novo acquisition of AML-specific enhancers. Altered enhancer dynamics are reflected in the gene expression of enhancer target genes, including genes involved in oncogenesis and blood cell development. This study demonstrates that histone variants and different histone modifications interact with aberrant DNA methylation and cause perturbed enhancer activity in cytogenetically normal AML that contributes to a leukemic transcriptome.
Keywords:	DNA Methylation, Enhancer of Transcription, Cancer, Histones, Chromatin, Leukemia, Methylation
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	129
Number:	7
Page Range:	e13-e25
Date:	16 February 2017
Official Publication:	https://doi.org/10.1182/blood-2016-07-726877
PubMed:	View item in PubMed

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