Changes of 5-hydroxymethylcytosine distribution during myeloid and lymphoid differentiation of CD34+ cells

Xavier Tekpli; Alfonso Urbanucci; Adnan Hashim; Cathrine B Vågbø; Robert Lyle; Marianne K Kringen; Anne Cathrine Staff; Ingunn Dybedal; Ian G Mills; Arne Klungland; Judith Staerk

doi:10.1186/s13072-016-0070-8

Changes of 5-hydroxymethylcytosine distribution during myeloid and lymphoid differentiation of CD34+ cells

Epigenetics Chromatin. 2016 May 31:9:21. doi: 10.1186/s13072-016-0070-8. eCollection 2016.

Authors

Affiliations

¹ Nordic European Molecular Laboratory (EMBL) Partnership, Centre for Molecular Medicine Norway, University of Oslo, Blindern, P.O. Box 1137, 0318 Oslo, Norway ; Department of Genetics, Institute for Cancer Research, Oslo University Hospital - The Norwegian Radium Hospital, Oslo, Norway.
² Nordic European Molecular Laboratory (EMBL) Partnership, Centre for Molecular Medicine Norway, University of Oslo, Blindern, P.O. Box 1137, 0318 Oslo, Norway ; Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
³ Nordic European Molecular Laboratory (EMBL) Partnership, Centre for Molecular Medicine Norway, University of Oslo, Blindern, P.O. Box 1137, 0318 Oslo, Norway.
⁴ Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
⁵ Department of Medical Genetics, University of Oslo, Oslo University Hospital, Oslo, Norway.
⁶ Department of Pharmacology, Oslo University Hospital, Ullevål, Oslo, Norway.
⁷ Department of Obstetrics and Gynecology, Oslo University Hospital, University of Oslo, Oslo, Norway.
⁸ Department of Haematology, Oslo University Hospital, Oslo, Norway.
⁹ Nordic European Molecular Laboratory (EMBL) Partnership, Centre for Molecular Medicine Norway, University of Oslo, Blindern, P.O. Box 1137, 0318 Oslo, Norway ; Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway ; PCUK Movember Centre of Excellence, CCRCB, Queen's University, Belfast, UK.
¹⁰ Clinic for Diagnostics and Intervention, Institute of Medical Microbiology, Oslo University Hospital, University of Oslo, Oslo, Norway ; Norwegian Center for Stem Cell Research, University of Oslo, Oslo, Norway.
¹¹ Nordic European Molecular Laboratory (EMBL) Partnership, Centre for Molecular Medicine Norway, University of Oslo, Blindern, P.O. Box 1137, 0318 Oslo, Norway ; Department of Haematology, Oslo University Hospital, Oslo, Norway ; Norwegian Center for Stem Cell Research, University of Oslo, Oslo, Norway.

Abstract

Background: Hematopoietic stem cell renewal and differentiation are regulated through epigenetic processes. The conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5hmC) by ten-eleven-translocation enzymes provides new insights into the epigenetic regulation of gene expression during development. Here, we studied the potential gene regulatory role of 5hmC during human hematopoiesis.

Results: We used reduced representation of 5-hydroxymethylcytosine profiling (RRHP) to characterize 5hmC distribution in CD34+ cells, CD4+ T cells, CD19+ B cells, CD14+ monocytes and granulocytes. In all analyzed blood cell types, the presence of 5hmC at gene bodies correlates positively with gene expression, and highest 5hmC levels are found around transcription start sites of highly expressed genes. In CD34+ cells, 5hmC primes for the expression of genes regulating myeloid and lymphoid lineage commitment. Throughout blood cell differentiation, intragenic 5hmC is maintained at genes that are highly expressed and required for acquisition of the mature blood cell phenotype. Moreover, in CD34+ cells, the presence of 5hmC at enhancers associates with increased binding of RUNX1 and FLI1, transcription factors essential for hematopoiesis.

Conclusions: Our study provides a comprehensive genome-wide overview of 5hmC distribution in human hematopoietic cells and new insights into the epigenetic regulation of gene expression during human hematopoiesis.

Keywords: 5-Hydroxymethylcytosine; Epigenetics; FLI1; Hematopoiesis; RUNX.