Regulatory Circuitries Coordinated by Transcription Factors and microRNAs at the Cornerstone of Hematopoietic Stem Cell Self-Renewal and Differentiation

In mammals, hematopoiesis is the continuous formation of all blood cell types from a limited pool of hematopoietic stem cells (HSCs) residing in specialized niches in the bone marrow (BM). Hierarchical specification of hematopoietic lineages, as well as stem cell kinetics, are dynamic processes influenced by an intricate network of soluble growth factors and membrane-anchored signals orchestrated by the microenvironment (extrinsic signals), coupled with cell-autonomous changes in gene expression (intrinsic signals). At the molecular level, during the early steps of hematopoietic differentiation from the HSC, the chromatin progressively becomes more accessible at genes poised for expression, rapidly followed by an increased expression of lineage-associated genes with concomitant repression of alternativelineage genes, resulting in commitment and differentiation. These events are established by the coordinated action of transcription factors (TFs), chromatin remodeling factors and microRNAs (miRNAs). In this review we describe the combinatorial molecular circuitries managed by TFs and miRNAs underlying HSC emergence, maintenance and lineage development.