Uncovering network control of blood cell production

Blood stem and progenitor cells are responsible for the constant production of red and white blood cells, and also platelets, with millions of these blood cells being produced every second. Disruption of this blood cell production system can lead to diseases such as leukaemia, a type of blood cancer caused by a rapid overproduction of abnormal white blood cells.

The process of producing blood cells from stem and progenitor cells is immensely complex, involving networks comprising thousands of genes, proteins and other molecules which interact with each other. However, our understanding of these networks and signalling pathways has thus far been somewhat limited.

In new research published today in EMBO journal, scientists at the Wellcome – MRC Cambridge Stem Cell Institute, in collaboration with scientists from the Max Planck Institute in Freiburg, Germany, used a novel approach to dissect these networks piece by piece, with a particular focus on transcription factors, key regulators of blood stem and progenitor cells.

The researchers used new gene editing technology (CRISPR/Cas9) to disable 39 transcription factors (chosen for their known important roles in blood cell production) and measured the knock-on effects on global gene activity using RNA-Seq technology. The results identified ~17,000 new functional links connecting transcription factors and their target genes. This information established a novel subnetwork which sheds new light on the mechanisms driving progenitor cell growth and shows how cells maintain the ability to generate different blood cell types by balancing levels of transcription factors associated with each possible outcome.

Building a complex network to understand how blood cell production is controlled. Orange dots: 39 transcription factors that were manually disrupted in the study. Grey dots: 1000s of genes regulated by these transcription factors. Red and blue linking lines indicate genetic activation (blue) and repression (red).

Trying to understand the importance and biological relevance of such large datasets is a major challenge. “To help attribute biological functions to the factors of interest, we developed ‘DoT score’, a new computer program which aids visualisation and interpretation of complex transcriptomic datasets” explains Prof Bertie Göttgens, whose team carried out the research.  “Using previous genetic findings as a reference, DoT score has transformed our ability to interpret large-scale perturbation studies, and in this case, enhance our understanding of the blood cell production system”. 

Through the use of their new DoT score computer program, the researchers undertook focussed analysis of their new gene network, and identified a range of gene systems associated with specific functions in the blood progenitor cells. DoT score will be made available to any researcher wanting to interrogate large-datasets, and will enable interpretation of gene functions across a wide variety of settings, thus driving further discoveries.

“There is a long way ahead of us to fully grasp the molecular networks driving blood cell production” explained Dr Iwo Kucinski, lead researcher on the project. “But each discovered functional link brings us a step closer towards targeted engineering of cellular behaviour to suit therapeutic needs in diseases such as leukaemia.”

Reference
Kucinski et al. Interactions betweenlineage-associated transcription factors govern haematopoietic progenitor states. EMBO J (2020) e104983

Funding
The support of Wellcome, Medical Research Council, Blood Cancer UK, Cancer Research UK and National Institutes of Health* are gratefully acknowledged by the team.   * Research reported in this press release was supported by the National Institutes of Health under award number NIDDK DK106766 to a value of $5,000 worth of work, against a total project cost of $800,000.