High resolution methylome analysis reveals widespread functional hypomethylation during adult human erythropoiesis

Yiting Yu, Yongkai Mo, David Ebenezer, Sanchari Bhattacharyya, Hui Liu, Sriram Sundaravel, Orsolya Giricz, Sandeep Wontakal, Jessy Cartier, Bennett Caces, Andrew Artz, Sangeeta Nischal, Tushar Bhagat, Kathleen Bathon, Shahina Maqbool, Oleg Gligich, Masako Suzuki, Ulrich Steidl, Lucy Godley, Art SkoultchiJohn Greally, Amittha Wickrema, Amit Verma

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Differentiation of hematopoietic stem cells to red cells requires coordinated expression of numerous erythroid genes and is characterized by nuclear condensation and extrusion during terminal development. To understand the regulatory mechanisms governing these widespread phenotypic changes, we conducted a high resolution methylomic and transcriptomic analysis of six major stages of human erythroid differentiation. We observed widespread epigenetic differences between early and late stages of erythropoiesis with progressive loss of methylation being the dominant change during differentiation. Gene bodies, intergenic regions, and CpG shores were preferentially demethylated during erythropoiesis. Epigenetic changes at transcription factor binding sites correlated significantly with changes in gene expression and were enriched for binding motifs for SCL, MYB, GATA, and other factors not previously implicated in erythropoiesis. Demethylation at gene promoters was associated with increased expression of genes, whereas epigenetic changes at gene bodies correlated inversely with gene expression. Important gene networks encoding erythrocyte membrane proteins, surface receptors, and heme synthesis proteins were found to be regulated by DNA methylation. Furthermore, integrative analysis enabled us to identify novel, potential regulatory areas of the genome as evident by epigenetic changes in a predicted PU.1 binding site in intron 1 of the GATA1 gene. This intronic site was found to be conserved across species and was validated to be a novel PU.1 binding site by quantitative ChIP in erythroid cells. Altogether, our study provides a comprehensive analysis of methylomic and transcriptomic changes during erythroid differentiation and demonstrates that human terminal erythropoiesis is surprisingly associated with hypomethylation of the genome.

Original languageEnglish (US)
Pages (from-to)8805-8814
Number of pages10
JournalJournal of Biological Chemistry
Volume288
Issue number13
DOIs
StatePublished - Mar 29 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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