Analysis of the DNA methylome and transcriptome in granulopoiesis reveals timed changes and dynamic enhancer methylation

Rönnerblad, Michelle; Andersson, Robin; Olofsson, Tor; Douagi, Iyadh; Karimi, Mohsen; Lehmann, Sören; Hoof, Ilka; Hoon, Michiel de; Itoh, Masayoshi; Nagao-Sato, Sayaka; Kawaji, Hideya; Lassmann, Timo; Carninci, Piero; Hayashizaki, Yoshihide; Forrest, Alistair R.R.; Sandelin, Albin; Ekwall, Karl; Arner, Peter; Lennartsson, Andreas

doi:10.1182/blood-2013-02-482893

Cited by 76 publications

(77 citation statements)

References 48 publications

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“…16 We confirmed that the main changes in DNA methylation occur between GMPs and PMCs, as previously reported (supplemental Figure 2A-C). 16 The two progenitor populations (CMPs and GMPs) show very similar DNA methylation patterns, with very few differentially methylated CpG sites (DMCs) (supplemental Figure 2A). Consequently, comparing DNA methylation in CN-AML to either CMPs or GMPs showed very similar results (supplemental Figure 2D-E).…”

Section: Dna Methylation Changes In Cn-amlsupporting

confidence: 78%

“…15,16 The research was approved by the ethical committee in Stockholm, Sweden. Genomic characterization by mutational analysis was performed as previously described.…”

Section: Bone Marrow Samples From Patients and Healthy Donorsmentioning

confidence: 99%

“…Genomic DNA samples were extracted and used as previously described. 15,16 A cohort from The Cancer Genome Atlas was used for validation. 4 For further information, including correlation with overall survival and pyrosequencing validation, see supplemental Data.…”

Section: Bone Marrow Samples From Patients and Healthy Donorsmentioning

confidence: 99%

“…Genomic characterization by mutational analysis was performed as previously described. 15,16 DNA methylation analysis Genome-wide DNA methylation levels were detected by Illumina's Human Methylation 450k Array. Genomic DNA samples were extracted and used as previously described.…”

Section: Bone Marrow Samples From Patients and Healthy Donorsmentioning

confidence: 99%

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

Siggens

Cordeddu

et al. 2017

Blood

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Key Points• DNA demethylation activates new and poised enhancers in AML that cause a leukemic transcriptome.• Only a subset of DNA demethylated enhancers becomes activated. A specific additional activation step is required for enhancer activation.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. (Blood. 2017;129(7):e13-e25)

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Section: Dna Methylation Changes In Cn-amlsupporting

confidence: 78%

“…15,16 The research was approved by the ethical committee in Stockholm, Sweden. Genomic characterization by mutational analysis was performed as previously described.…”

Section: Bone Marrow Samples From Patients and Healthy Donorsmentioning

confidence: 99%

Section: Bone Marrow Samples From Patients and Healthy Donorsmentioning

confidence: 99%

Section: Bone Marrow Samples From Patients and Healthy Donorsmentioning

confidence: 99%

See 2 more Smart Citations

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

Siggens

Cordeddu

et al. 2017

Blood

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“…GSE50797 (Rönnerblad et al 2014) three adult bone marrow samples were used to isolate two different CD34 Table S1.…”

Section: Cd34mentioning

confidence: 99%

Tracing human stem cell lineage during development using DNA methylation

et al. 2018

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Abstract:Stem cell maturation is a fundamental, yet poorly understood aspect of human development. We devised a DNA methylation signature deeply reminiscent of embryonal stem cells (a fetal cell origin signature, FCO) to interrogate the evolving character of multiple human tissues. The cell fraction displaying this FCO signature was highly dependent upon developmental stage (fetal vs adult), and in leukocytes, it described a dynamic transition during the first 5 years of life. Significant individual variation in the FCO signature of leukocytes was evident at birth, in childhood, and throughout adult life. The genes characterizing the signature included transcription factors and proteins intimately involved in embryonic development. We defined and applied a DNA methylation signature common among human fetal hematopoietic progenitor cells, and have shown that this signature traces the lineage of cells and informs the study of stem cell heterogeneity in humans under homeostatic conditions.

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Enhancer deregulation in cancer and other diseases

Herz

2016

BioEssays

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Summary Mutations in enhancer-associated chromatin-modifying components and genomic alterations in non-coding regions of the genome occur frequently in cancer and other diseases pointing to the importance of enhancer fidelity to ensure proper tissue homeostasis. In this review, I will use specific examples to discuss how mutations in chromatin-modifying factors might affect enhancer activity of disease-relevant genes. I will then consider direct evidence from single nucleotide polymorphisms, small insertions or deletions but also larger genomic rearrangements such as duplications, deletions, translocations and inversions of specific enhancers to demonstrate how they have the ability to impact enhancer activity of disease genes including oncogenes and tumor suppressor genes. Considering that the scientific community only fairly recently has begun to focus its attention on “enhancer malfunction” in disease, I propose that multiple new enhancer-regulated and disease-relevant processes will be uncovered in the near future that will constitute the mechanistic basis for novel therapeutic avenues.

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Analysis of the DNA methylome and transcriptome in granulopoiesis reveals timed changes and dynamic enhancer methylation

Cited by 76 publications

References 48 publications

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

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

Tracing human stem cell lineage during development using DNA methylation

Enhancer deregulation in cancer and other diseases

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