Publication Date:
2013-12-28
Description:
Publication date: Available online 26 December 2013 Source: Cell Reports Author(s): 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. Levine , Don Lavelle , Bruce T. Lahn , Amittha Wickrema , Lucy A. Godley 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. Graphical abstract Teaser 5-hydroxymethylcytosine (5-hmC) is a DNA modification catalyzed by the TET enzymes. The significance of this modification is not completely defined, but it is known to be dysregulated in hematological malignancies. In this study, Wickrema, Godley, and colleagues demonstrate that 5-hmC plays an important role in hematopoietic stem cell commitment to the erythroid lineage and is associated with activating histone marks at a genome-wide level. TET2 deficiency disrupts 5-hmC patterns and compromises erythroid differentiation.
Electronic ISSN:
2211-1247
Topics:
Biology
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