Hydroxymethylation at gene regulatory regions directs stem/early progenitor cell commitment during erythropoiesis

Jozef Madzo, Hui Liu, Alexis Rodriguez, Aparna Vasanthakumar, Sriram Sundaravel, Donne Bennett D. Caces, Timothy J. Looney, Li Zhang, Janet B. Lepore, Trisha Macrae, Robert Duszynski, Alan H. Shih, Chun Xiao Song, Miao Yu, Yiting Yu, Robert Grossman, Brigitte Raumann, Amit Verma, Chuan He, Ross L. LevineDon Lavelle, Bruce T. Lahn, Amittha Wickrema, Lucy A. Godley

Research output: Contribution to journalArticlepeer-review

88 Scopus citations


Hematopoietic stem cell differentiation involves the silencing of self-renewal genes and induction of a specific transcriptional program. Identification of multiple covalent cytosine modifications raises the question of how these derivatized bases influence stem cell commitment. Using a replicative primary human hematopoietic stem/progenitor cell differentiation system, we demonstrate dynamic changes of 5-hydroxymethylcytosine (5-hmC) during stem cell commitment and differentiation to the erythroid lineage. Genomic loci that maintain or gain 5-hmC density throughout erythroid differentiation contain binding sites for erythroid transcription factors and several factors not previously recognized as erythroid-specific factors. The functional importance of 5-hmC was demonstrated by impaired erythroid differentiation, with augmentation of myeloid potential, and disrupted 5-hmC patterning in leukemia patient-derived CD34+ stem/early progenitor cells with TET methylcytosine dioxygenase 2 (TET2) mutations. Thus, chemical conjugation and affinity purification of 5-hmC-enriched sequences followed by sequencing serve as resources for deciphering functional implications for gene expression during stem cell commitment and differentiation along a particular lineage.

Original languageEnglish
Pages (from-to)231-244
Number of pages14
JournalCell Reports
Issue number1
StatePublished - 2014
Externally publishedYes


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