Dynamic DNA methylation reveals novel cis-regulatory elements in murine hematopoiesis

Abstract

BackgroundThe differentiation of hematopoietic stem and progenitor cells (HSPCs) to terminally differentiated immune cells is accompanied by large-scale remodeling of the DNA methylation landscape. While significant insights into the molecular mechanisms of hematopoietic tissue regeneration were derived from mouse models, profiling of DNA methylation changes has been hampered by high cost or low resolution using the methods available. This problem has been overcome by the recent development of the Infinium Mouse Methylation BeadChip (MMBC) array, facilitating methylation profiling of the mouse genome at single CpG resolution at affordable cost. ResultsWe extended the RnBeads package to provide a computational framework for the analysis of MMBC data. This framework was applied to a newly generated MMBC reference map of mouse hematopoiesis encompassing nine different cell types. The analysis of dynamically regulated CpG sites showed progressive and unidirectional DNA methylation changes from HSPCs to differentiated hematopoietic cells and allowed the identification of lineage- and cell type-specific DNA methylation programs. Comparison to previously published catalogues of cis-regulatory elements (CREs) revealed 12,856 novel putative CREs which were dynamically regulated by DNA methylation (mdCREs). These mdCREs were predominantly associated with patterns of cell type-specific DNA hypomethylation and could be identified as epigenetic control regions regulating the expression of key hematopoietic genes during differentiation. ConclusionsWe established a publicly available analysis pipeline for MMBC datasets and provide a DNA methylation atlas of mouse hematopoiesis. This resource allowed us to identify novel putative CREs involved in hematopoiesis and will serve as a platform to study epigenetic regulation of normal and malignant hematopoiesis.