Hierarchical chromatin regulation during blood formation uncovered by single-cell sortChIC

Post-translational histone modifications modulate chromatin packing to regulate gene expression. How chromatin states, both at euchromatic and at heterochromatic regions, underlie cell fate decisions in single cells is relatively unexplored. We develop sort assisted single-cell chromatin immunocleavage (sortChIC) and apply it to map active (H3K4me1 and H3K4me3) and repressive (H3K27me3 and H3K9me3) histone modifications in hematopoietic stem and progenitor cells (HSPCs), and mature blood cells in the mouse bone marrow. During differentiation, HSPCs acquire distinct active chromatin states that depend on the specific cell fate, mediated by cell type-specifying transcription factors. By contrast, most regions that gain or lose repressive marks during differentiation do so independent of the specific cell fate. Joint profiling of active H3K4me1 and repressive H3K9me3 in single cells demonstrates that cell types within the myeloid lineage have distinct active chromatin regulation but share a similar myeloid-specific heterochromatin-repressed state. Our results suggest a hierarchical chromatin regulation program during hematopoiesis, by which heterochromatin dynamics define differentiation trajectories and lineages, while euchromatin dynamics establish cell types within lineages. single-cell sortChIC data on K562 and mouse bone marrow cells