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Cell Rep. 2014 Jan 16;6(1):231-244. doi: 10.1016/j.celrep.2013.11.044. Epub 2013 Dec 27.

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

Author information

1
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
2
Center for Research Informatics, The University of Chicago, Chicago, IL 60637, USA.
3
Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
4
Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA.
5
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
6
Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA.
7
Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
8
Albert Einstein College of Medicine, Bronx, NY 10461, USA.
9
Department of Medicine, University of Illinois, Chicago, Chicago, IL 60612, USA.
10
Jesse Brown VA Medical Center, Chicago, IL 60612, USA.
#
Contributed equally

Abstract

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.

PMID:
24373966
PMCID:
PMC3976649
DOI:
10.1016/j.celrep.2013.11.044
[Indexed for MEDLINE]
Free PMC Article
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