Cell Stem Cell. 2016 Nov 16. pii: S1934-5909(16)30360-5. doi: 10.1016/j.stem.2016.10.019. [Epub ahead of print]

DNA Methylation Dynamics of Human Hematopoietic Stem Cell Differentiation.

Farlik M¹, Halbritter F¹, Müller F², Choudry FA³, Ebert P², Klughammer J¹, Farrow S³, Santoro A⁴, Ciaurro V⁴, Mathur A⁵, Uppal R⁵, Stunnenberg HG⁶, Ouwehand WH⁷, Laurenti E⁸, Lengauer T⁹, Frontini M¹⁰, Bock C¹¹.

Abstract

Hematopoietic stem cells give rise to all blood cells in a differentiation process that involves widespread epigenome remodeling. Here we present genome-wide reference maps of the associated DNA methylation dynamics. We used a meta-epigenomic approach that combines DNA methylation profiles across many small pools of cells and performed single-cell methylome sequencing to assess cell-to-cell heterogeneity. The resulting dataset identified characteristic differences between HSCs derived from fetal liver, cord blood, bone marrow, and peripheral blood. We also observed lineage-specific DNA methylation between myeloid and lymphoid progenitors, characterized immature multi-lymphoid progenitors, and detected progressive DNA methylation differences in maturing megakaryocytes. We linked these patterns to gene expression, histone modifications, and chromatin accessibility, and we used machine learning to derive a model of human hematopoietic differentiation directly from DNA methylation data. Our results contribute to a better understanding of human hematopoietic stem cell differentiation and provide a framework for studying blood-linked diseases.