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

Abstract

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

An Epigenome-Wide DNA Methylation Map of Testis in Pigs for Study of Complex Traits

“…We found that approximately 69% of DMCs associated with CpG islands were located in promoter regions (Table 2). Liu et al (Liu et al, 2017) reported that the proportions of hypermethylated CpG sites located in CpG islands, CpG shores and other locations were 25.49∼34.23%, 21.57∼40.75%, and 25.02∼52.94%, respectively, during different stages of human embryonic stem cells. Genes that contained differentially methylated regions (DMRs) in their first intron were more than the genes that contained DMRs in their promoter and their first exon (Anastasiadi et al, 2018), which are the same trend as this study (Supplementary File S1).…”

The JAK/STAT Pathway in Skeletal Muscle Pathophysiology

“…Moreover, an association between IL6/JAK/STAT DNA altered methylation and depression has been recently described (Ryan et al., 2017). JAK and STAT gene hypomethylation might also exert influences on erythroid lineage choice by specifically upregulating erythropoiesis transcription factors (Liu et al., 2017). In B cells activating pathway, the lysine-specific histone methyltransferase KMT2D affected H3K4 methylation and expression of a specific set of JAK-STAT genes (Figure 2B; Ortega-Molina et al., 2015).…”

Multiomics analyses identified epigenetic modulation of the S100A gene family in Kawasaki disease and their significant involvement in neutrophil transendothelial migration

“…Previous studies have demonstrated that abnormal DNA methylation led to gastric carcinogenesis by either hyper-methylating several tumor-suppressive miRNAs [ 3 – 5 ] or hypo-methylating onco-miR [ 6 ]. In addition, DNA methylation also regulated the erythropoiesis of embryonic stem cell [ 7 ], the pathogenesis of idiopathic pulmonary fibrosis [ 8 ], the neurodevelopment of the human hippocampus [ 9 ], and other processes. In addition to regulating disease pathogenesis, DNA methylation also performs long-term regulatory activities.…”