Regulatory network control of blood stem cells

Abstract

Hematopoietic stem cells (HSCs) are characterized by their ability to execute a wide range of cell fate choices, including selfrenewal, quiescence, and differentiation into the many different mature blood lineages. Cell fate decision making in HSCs, as indeed in other cell types, is driven by the interplay of external stimuli and intracellular regulatory programs. Given the pivotal nature of HSC decision making for both normal and aberrant hematopoiesis, substantial research efforts have been invested over the last few decades into deciphering some of the underlying mechanisms. Central to the intracellular decision making processes are transcription factor proteins and their interactions within gene regulatory networks. More than 50 transcription factors have been shown to affect the functionality of HSCs. However, much remains to be learned about the way in which individual factors are connected within wider regulatory networks, and how the topology of HSC regulatory networks might affect HSC function. Nevertheless, important progress has been made in recent years, and new emerging technologies suggest that the pace of progress is likely to accelerate. This review will introduce key concepts, provide an integrated view of selected recent studies, and conclude with an outlook on possible future directions for this field. (Blood. 2015;125(17):2614-2620 Building blocks of transcriptional regulatory networksThe primary components of transcriptional regulatory networks are transcription factor (TF) proteins and the gene regulatory DNA sequences that they bind to.1 By binding to specific DNA sequence motifs within gene regulatory regions, TF proteins are central players for this primary step of decoding gene regulatory instructions. TF proteins typically contain a number of distinct modules, such as DNA binding, transcriptional activation, and protein/protein interaction domains, with the latter 2 being essential for the recruitment of the basal transcriptional machinery and the assembly of higherorder TF complexes. Based on sequence similarity within the DNA binding domain, TF proteins can be categorized into distinct families, such as homeobox, basic helix-loop-helix, or zinc finger TFs. Members of a given TF family often bind to similar DNA sequences, and proteinprotein interactions are common both within and between the different TF families.Individual TFs bind short sequence motifs that are often no longer than 4 to 6 bp. Any given 6-bp sequence will occur on average approximately once every 4000 bp. Consequently, there will be ;750 000 occurrences just by chance within the 3 000 000 000 bp of the human genome. The number of possible binding sites therefore far exceeds the 20 000 or so human genes, and it has long been assumed that only a small minority of all motif instances play a role in transcriptional regulation. Functional gene regulatory regions should therefore display characteristics that go beyond the mere occurrence of a specific sequence motif. One such characteristic is the presence of clusters of b...

Mammalian Transcription Factor Networks: Recent Advances in Interrogating Biological Complexity

“…While TF networks have been investigated in numerous mammalian cell types, such networks have been most intensively studied in pluripotent stem cells (Ng and Surani, 2011, Orkin et al, 2008), adult muscle stem cells (Buckingham and Rigby, 2014, Tapscott, 2005), and adult hematopoietic stem cells (Göttgens, 2015) (Figure 4). Additionally, TF network dysregulation is a common theme in cancer, particularly leukemia (Sive and Gottgens, 2014).…”

Chromatin dynamics during the differentiation of long-term hematopoietic stem cells to multipotent progenitors

“…5 Much progress has been made to understand the regulatory network of HSC self-renewal and differentiation. 6,7 Several studies suggest that epigenetic mechanisms play an important role in controlling HSC renewal and lineage commitment. [8][9][10][11][12] Understanding the regulatory mechanisms of HSC self-renewal and differentiation is important for both basic stem cell biology and improving the quality of stem cell transplantation in clinical settings.…”

PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells

“…Investigations have largely focused on extracellular signals, and also on roles of transcription, chromatin, and noncoding RNA regulators. [1][2][3][4] In contrast to the understanding of transcriptional networks regulating HSPC fate, the role of posttranscriptional events in this process remains poorly studied. The HOXB4 homeoprotein is a major expansion factor of mouse and human HSPCs, as we and others have shown.…”