High Resolution Methylome Analysis Reveals Widespread Functional Hypomethylation during Adult Human Erythropoiesis

Yu, Yiting; Mo, Yongkai; Ebenezer, David L.; Bhattacharyya, Sanchari; Liu, Hui; Sundaravel, Sriram; Giricz, Orsi; Wontakal, Sandeep N.; Cartier, Jessy; Caces, Bennett; Artz, Andrew S.; Nischal, Sangeeta; Bhagat, Tushar D.; Bathon, Kathleen; Maqbool, Shahina; Gligich, Oleg; Suzuki, Masako; Steidl, Ulrich; Godley, Lucy A.; Skoultchi, A; Greally, John M.; Wickrema, Amittha; Verma, Amit

doi:10.1074/jbc.m112.423756

Cited by 39 publications

(54 citation statements)

References 25 publications

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“…Moreover, according to a recent study, methylation is most relevant at the HSC level but less so after lineage commitment [11]. As determined using Dnmt3a −/− and Dnmt3b −/− HSCs, de novo methylation is important for HSC renewal but not for differentiation [12]; this notion is further supported by a recent study examining the differentiation of CD34 + cells into reticulocytes that compared early and late erythroid progenitors, revealing progressive hypomethylation to be the predominant change in DNA methylation [13]. Thus, DNA demethylation is an essential epigenetic mechanism for erythroid differentiation programs in both ESCs and HSCs.…”

supporting

confidence: 64%

“…However, regions outside of the promoters, as well as non-CpG island loci, are also very important for transcriptional regulation [16,17]. For example, a study examining erythropoiesis from CD34 + stem/hematopoietic cells revealed preferential progressive hypomethylation in gene bodies, intergenic regions and CpG shores; moreover, gene body hypomethylation was associated with decreased gene expression, in contrast to the effects of hypomethylation at promoters [13]. The true role of methylation changes in different genomic contexts must still be explored, taking into account numerous hypomethylation events -particularly at distinct differentiation stages.…”

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confidence: 99%

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Genome-Wide Dna Methylation Drives Human Embryonic Stem Cell Erythropoiesis by Remodeling Gene Expression Dynamics

Liu

Feng²,

Sun

et al. 2017

Epigenomics

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Aim:To investigate the role of DNA methylation during erythrocyte production by human embryonic stem cells (hESCs). Methods: We employed an erythroid differentiation model from hESCs, and then tracked the genome-wide DNA methylation maps and gene expression patterns through an Infinium HumanMethylation450K BeadChip and an Ilumina Human HT-12 v4 Expression Beadchip, respectively. Results: A negative correlation between DNA methylation and gene expression was substantially enriched during the later differentiation stage and was present in both the promoter and the gene body. Moreover, erythropoietic genes with differentially methylated CpG sites that were primarily enriched in nonisland regions were upregulated, and demethylation of their gene bodies was associated with the presence of enhancers and DNase I hypersensitive sites. Finally, the components of JAK-STAT-NF-κB signaling were DNA hypomethylated and upregulated, which targets the key genes for erythropoiesis. Conclusion: Erythroid lineage commitment by hESCs requires genome-wide DNA methylation modifications to remodel gene expression dynamics. Erythrocyte transfusion is useful for many patients with hematological disorders or emergencies. As erythrocyte supply depends on limited voluntary donations and involves the risk of infectious disease transmission, human embryonic stem cells (hESCs) are ideal candidates for in vitro erythropoiesis due to their nonimmunoreactive nature and limitless quantities [1][2][3]. However, many technical obstacles must be overcome to achieve single-lineage differentiation. Thus, understanding the mechanisms governing pluripotent stem cell erythropoiesis is highly important.DNA methylation at CpG dinucleotide, which constitutes the most important epigenetic modification, regulates the gene expression dynamics of transcription factors during erythropoiesis [4]. However, the role of total-genome DNA methylation in determining stem cell fate and erythroid-lineage commitment remains poorly understood. Employing large-scale DNA methylation mapping, some in vivo studies have uncovered the changes in DNA methylation during hematopoietic stem cell (HSC) or hematopoietic progenitor cell differentiation and lineage commitment [4][5][6][7], and in vitro studies have revealed hypomethylation events that occur during erythropoiesis [4,8], although some studies directly comparing differentiated cell types have detected virtually no demethylation during cellular differentiation, indicating increased DNA methylation-mediated epigenetic repression during lineage specification [9,10]. Therefore, hypomethylation may be more significant for erythropoiesis than the development of other cell type. Moreover, according to a recent study, methylation is most relevant at the HSC level but less so after

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supporting

confidence: 64%

mentioning

confidence: 99%

Genome-Wide Dna Methylation Drives Human Embryonic Stem Cell Erythropoiesis by Remodeling Gene Expression Dynamics

Liu

Feng²,

Sun

et al. 2017

Epigenomics

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“…For instance, it was recently shown that erythroid differentiation is accompanied by functional demethylation of essential erythropoietic genes, including GATA1 (6,55). In addition, maintenance of HSC programs and prevention of activation of differentiation programs are controlled by DNA methylation (8).…”

Section: Figurementioning

confidence: 99%

HSC commitment–associated epigenetic signature is prognostic in acute myeloid leukemia

Bartholdy¹,

Christopeit

Will³

et al. 2014

J. Clin. Invest.

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Acute myeloid leukemia (AML) is characterized by disruption of HSC and progenitor cell differentiation.Frequently, AML is associated with mutations in genes encoding epigenetic modifiers. We hypothesized that analysis of alterations in DNA methylation patterns during healthy HSC commitment and differentiation would yield epigenetic signatures that could be used to identify stage-specific prognostic subgroups of AML. We performed a nano HpaII-tiny-fragment-enrichment-by-ligation-mediated-PCR (nanoHELP) assay to compare genome-wide cytosine methylation profiles between highly purified human long-term HSC, short-term HSC, common myeloid progenitors, and megakaryocyte-erythrocyte progenitors. We observed that the most striking epigenetic changes occurred during the commitment of short-term HSC to common myeloid progenitors and these alterations were predominantly characterized by loss of methylation. We developed a metric of the HSC commitment-associated methylation pattern that proved to be highly prognostic of overall survival in 3 independent large AML patient cohorts, regardless of patient treatment and epigenetic mutations. Application of the epigenetic signature metric for AML prognosis was superior to evaluation of commitment-based gene expression signatures. Together, our data define a stem cell commitment-associated methylome that is independently prognostic of poorer overall survival in AML.

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“…DNA methylation is thought to provide a chemically stable mark that serves to initiate and reinforce these cell fate decisions. 2 Large-scale methylation studies of specific lineage pathways have been performed on differentiating erythroid, 3,4 T lymphocyte, 5,6 B lymphocyte, 7 and myeloid 4 cells. These important developmental studies reveal insights into the regulation of cell fate decisions but also serve as a potential source of biomarkers that help characterize different immune compartments during the immune response.…”

Section: Introductionmentioning

confidence: 99%

The DNA methylation profile of activated human natural killer cells

et al. 2016

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Natural killer (NK) cells are now recognized to exhibit characteristics akin to cells of the adaptive immune system. The generation of adaptive memory is linked to epigenetic reprogramming including alterations in DNA methylation. The study herein found reproducible genome wide DNA methylation changes associated with human NK cell activation. Activation led predominately to CpG hypomethylation (81% of significant loci). Bioinformatics analysis confirmed that non-coding and gene-associated differentially methylated sites (DMS) are enriched for immune related functions (i.e., immune cell activation). Known DNA methylation-regulated immune loci were also identified in activated NK cells (e.g., TNFA, LTA, IL13, CSF2). Twenty-one loci were designated high priority and further investigated as potential markers of NK activation. BHLHE40 was identified as a viable candidate for which a droplet digital PCR assay for demethylation was developed. The assay revealed high demethylation in activated NK cells and low demethylation in na€ ıve NK, T-and B-cells. We conclude the NK cell methylome is plastic with potential for remodeling. The differentially methylated region signature of activated NKs revealed similarities with T cell activation, but also provided unique biomarker candidates of NK activation, which could be useful in epigenome-wide association studies to interrogate the role of NK subtypes in global methylation changes associated with exposures and/or disease states.

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High Resolution Methylome Analysis Reveals Widespread Functional Hypomethylation during Adult Human Erythropoiesis

Cited by 39 publications

References 25 publications

Genome-Wide Dna Methylation Drives Human Embryonic Stem Cell Erythropoiesis by Remodeling Gene Expression Dynamics

Genome-Wide Dna Methylation Drives Human Embryonic Stem Cell Erythropoiesis by Remodeling Gene Expression Dynamics

HSC commitment–associated epigenetic signature is prognostic in acute myeloid leukemia

The DNA methylation profile of activated human natural killer cells

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