Epigenetic regulators of haematopoietic stem cells and their role in clonal haematopoiesis and aging

Elspeth Payne (primary)
Haematology, Cancer Institute
University College London
Kevin Bryson (secondary)
Computer Science
University College London

Abstract

Clonal haematopoiesis (CH) is common as we age, occurring in up to 50% of individuals over the age of 80. A significant proportion of such populations are driven by somatic mutations in critical epigenetic regulators most commonly ASXL1, TET2 and DNMT3A. Such populations confer an increase in all cause mortality, mainly from stroke, cardiovascular disease and cancer. In this project we use synthetic biology (Crispr/Cas9) in zebrafish to define the effects of mosaic somatic mutations in Asxl1, Dnmt3A and Tet2 in haematopoietic stem cells, and define the process of clonal dominance using single cell RNAseq, mathematical modelling and machine learning.


References

  1. Jaiswal S. et al Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014 Dec 25;371(26):2488–98.
  2. Berman J, Payne E, Hall C. The zebrafish as a tool to study hematopoiesis, human blood diseases, and immune function. Adv Hematol. 2012;2012:425345–2.
  3. Kiselev VY et al. SC3: consensus clustering of single-cell RNA-seq data. Nat Meth. 2017 May;14(5):483–6.
  4. Henninger J, et al Clonal fate mapping quantifies the number of haematopoietic stem cells that arise during development. Nat Cell Biol. 2017 Jan;19(1):17–27.
  5. Fuster JJ, et al. Clonal hematopoiesis associated with Tet2 deficiency accelerates atherosclerosis development in mice. Science.; 2017 Jan 19;:eaag1381.

BBSRC Area
Genes, development and STEM* approaches to biology
Area of Biology
AgeingGenetics
Techniques & Approaches
BioinformaticsGeneticsMathematics / StatisticsMolecular BiologySimulation / Modelling