Gene regulatory networks governing haematopoietic stem cell development and identity

Abstract

Development can be viewed as a dynamic progression through regulatory states which characterise the various cell types within a given differentiation cascade. To understand the progression of regulatory states that define the origin and subsequent development of haematopoietic stem cells, the first imperative is to understand the ontogeny of haematopoiesis. We are fortunate that the ontogeny of blood development is one of the best characterized mammalian developmental systems. However, the field is still in its infancy with regard to the reconstruction of gene regulatory networks and their interactions with cell signalling cascades that drive a mesodermal progenitor to adopt the identity of a haematopoietic stem cell and beyond. Nevertheless, a framework to dissect these networks and comprehend the logic of its circuitry does exist and although they may not as yet be available, a sense for the tools that will be required to achieve this aim is also emerging. In this review we cover the fundamentals of network architecture, methods used to reconstruct networks, current knowledge of haematopoietic and related transcriptional networks, current challenges and future outlook.

Identification of novel regulators of developmental hematopoiesis using Endoglin regulatory elements as molecular probes

“…[16][17][18] Endoglin (ENG) is an accessory receptor and modulator of TGF-b superfamily signaling. 19 ENG is expressed on FLK11 mesoderm and is required for normal BL-CFC development, and its expression facilitates the hematopoietic program in these cells.…”

A Runx1-Smad6 Rheostat Controls Runx1 Activity during Embryonic Hematopoiesis

“…At a transcriptional level, these regulatory modules anchor protein-DNA interactions within gene regulatory networks. Biological complexity does not scale with gene number but rather the intricacy of gene regulation, and the information-processing units that regulate gene expression in complex metazoans by and large reside not in gene promoters but in distal regulatory modules that can be recruited in a tissue-and cellspecific manner (29). This is evident in the Runx1-Smad6 rheostat, where the key functional interactions occur not at gene promoters (neither the Smad6 nor the Runx1 promoters are sufficient to target reporter expression to embryonic hematopoietic tissues in transgenic assays) but at distal enhancers.…”

“…Largely through the systematic analysis of transcription networks in bacteria and yeast, it is now known that information flow through complex networks is controlled by deploying a recurrent set of regulatory patterns called network motifs (1). Foremost among these are feed-forward and feed-back loops that regulate the temporal sequence and on/off kinetics of protein expression, which is essential for the coordinated growth of cells in metazoans (2,29).…”

“…Based on our current understanding, it is possible to construct a Smad6-Runx1 transcriptional circuit that integrates both the Bmp4 signaling cascade and the Fli1-Gata2-Scl triad linked via tissue-specific enhancers (Fig. 5A) (29). The activity of the Smad6-57 enhancer, which lacks a Runx binding motif, is dependent on an E-box/Gata motif.…”

MicroRNA-23a mediates post-transcriptional regulation of CXCL12 in bone marrow stromal cells

“…1,2 In recent years, it has become evident that the microenvironment of HSPC plays an additional crucial role in HSPC proliferation, differentiation, engraftment, and mobilization. 3,4 The supporting components of the hematopoietic niche have not yet been completely identified, but evidence is accumulating that several types of cells may be responsible for the interaction between HSPC and the hematopoietic niche.…”