Research at the HSCL

Transcriptional Control of Normal and Leukaemic Blood/Stem Progenitor Cells

Haematopoiesis has long served as a model system for studying the molecular processes that control cell fate decisions within complex differentiation cascades. The molecular control of haematopoiesis is underpinned by core circuits of regulatory networks, that when unified define the gene regulatory state of a particular cell. Core transcriptional regulatory circuits are composed of both transcription factors and the cis-regulatory elements they are bound to. Regulatory network reconstruction therefore requires the identification of cis-regulatory elements as well as the upstream factors which bind them.

The long term research goal of the Göttgens group is to decipher the molecular hierarchy of regulatory networks responsible for blood stem cell and endothelial development. To this end, the group uses complementary state-of-the-art approaches including embryonic stem cell and transgenic assays, bioinformatics, high throughput sequencing and mathematical modelling. The cumulative output of more than 40 research papers over the last 4 years has been the development of the most comprehensive network model for any adult stem cell type with over 40 transcription factors and more than 100 in vivo validated direct functional interactions. This integrated approach has resulted in the discovery of previously unrecognised combinatorial interactions between key regulators of blood stem cells with important implications for the transcriptional control of stem cell development and differentiation.

The importance of transcriptional control in both normal and leukaemic cells is underlined by the large number of transcription factor genes that cause leukaemia when disrupted or mutated. Future work will address how transcriptional programmes are perturbed in specific subtypes of leukaemia and may thus open up new avenues for the development of targeted therapies.

Funding: Leukaemia & Lymphoma Research, BBSRC, MRC, Cancer Research UK, Leukemia & Lymphoma Foundation USA, EU/Marie Curie, EMBO, NIHR, NC3Rs.
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