Submitted February 22, 2008
Accepted July 2, 2008
Lymphoid-affiliated genes are associated with active histone modifications in human hematopoietic stem cells
Jerome Maes, Marta Maleszewska, Claire Guillemin, Francoise Pflumio, Emmanuelle Six, Isabelle Andre-Schmutz, Marina Cavazzana-Calvo, Dominique Charron, Claire Francastel, and Michele Goodhardt*
Institut Universitaire d'Hematologie, Universite Paris, Paris, France
INSERM U662, Paris, France
CNRS UMR 8104, Institut Cochin, Universite Paris-Descartes, Paris, France
INSERM U567, Paris, France
INSERM U768, Paris, France
Universite Paris-Descartes, Faculte de Medecine Rene Descartes, Paris, France
* Corresponding author; email: michele.goodhardt{at}univ-paris-diderot.fr.
To address the role of chromatin structure in the establishment of hematopoietic stem cell (HSC) multilineage potential and commitment to the lymphoid lineage, we have analyzed histone modifications at a panel of lymphoid- and myeloid- affiliated genes in multipotent and lineage-committed hematopoietic cells isolated from human cord blood. Our results show that many B- and T-lymphoid genes, although silent in HSC, are associated with acetylated histones H3 and H4. We also detected histone H3 lysine 4 methylation, but not repressive lysine 9 or 27 methylation marks at these loci, indicative of an open chromatin structure. Interestingly, the relative level of H3 lysine 4 dimethylation to trimethylation at B-specific loci was high in multipotent CD34+CD38lo progenitors and decreased as they become actively transcribed in B-lineage cells. In vitro differentiation of CD34+ cells towards the erythroid, granulocyte and T cell lineages resulted in a loss of histone acetylation at non-lineage associated genes. This study provides evidence that histone modifications involved in chromatin decondensation are already in place at lymphoid-specific genes in primary human HSC, supporting the idea that these genes are "primed" for expression prior to lineage commitment. This permissive chromatin structure is progressively lost as the stem cell differentiates.
