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

Cell Rep 2014 Jan 27;6(1):231-244. Epub 2013 Dec 27.

Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.

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.

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http://dx.doi.org/10.1016/j.celrep.2013.11.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976649PMC
January 2014
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