Microtubules deform the nucleus and force chromatin reorganization during early differentiation of human hematopoietic stem cells

Hematopoietic stem cells (HSC) can differentiate into all hematopoietic lineages to support hematopoiesis. Cells from the myeloid and lymphoid lineages fulfill distinct functions with specific shapes and intra-cellular architectures. The role of cytokines in the regulation of HSC differentiation has been intensively studied but our understanding of the potential contribution of inner cell architecture is relatively poor. Here we show that large invaginations are generated by microtubule constraints on the swelling nucleus of human HSCs during early commitment toward the myeloid lineage. These invaginations are associated with chromatin reorganization, local loss of H3K9 trimethylation and changes in expression of specific hematopoietic genes. This establishes the role of microtubules in defining the unique lobulated nuclear shape observed in myeloid progenitor cells and suggests that this shape is important to establish the gene expression profile specific to this hematopoietic lineage. It opens new perspectives on the implications of microtubule-generated forces, in the early specification of the myeloid lineage.