BSc (Hons) DPhil
Senior Postdoctoral Researcher
Researching the genetic basis of anaemia, alpha-globin gene regulation and haemoglobin switching.
My research focuses on the genetic causes of anaemia, regulation of the alpha globin locus and haemoglobin switching.
Genetic Causes of Anaemia
Anaemia results from the failure of adequate production of red blood cells in the bone marrow or insufficient production of the oxygen carrying metalloprotein haemoglobin. This can be a distressing condition and I am a board member and supporter of the charity The Congenital Anaemia Network. Currently ~60% of patients with congenital anaemia remain without a genetic diagnosis and part of my research utilises next generation sequencing technologies to identify novel causative variants and broaden the diagnostic range for these disorders. As part of this work I have identified a novel gene, C15ORF41, underlying a type of anaemia termed Congenital Dyserythropoietic Anaemia type I (CDA-I) (Babbs et al., 2013).
Only one other gene is known to underlie CDA-I, CDAN1 encoding the protein Codanin-1. Both C15ORF41 and Codanin-1 are widely expressed and highly conserved yet when either is mutated phenotypic abnormalities are present only in red blood cells. We are building on evidence that Codanin-1 and C15ORF41 interact and play a role in a novel pathway affecting DNA replication or chromatin assembly. We are working to identify the other proteins involved in this pathway in normal erythropoiesis and how, when perturbed, it leads to the specific abnormalities seen in CDA-I. This work is funded in part by Action medical Research for Children and the Henry Smith Charity.
Haemoglobin Switching: Anaemia can also arise as a result of insufficient production of haemoglobin, a tetrameric protein consisting of two alpha-like and two beta-like globin chains.
At least 340,000 individuals with severe inherited disorders of haemoglobin are born each year. Of these ~70,000 suffer from alpha- or beta-thalassaemia, which are the most common human monogenic disorders known with a carrier rate of >1% among all tropical and subtropical populations studied. The major treatment for severe alpha-thalassemia is symptomatic care and transfusion of red blood cells as clinically necessary. However, the use of regular blood transfusions can give rise to significant problems.
The only potentially curative therapies currently available for severe alpha-thalassemia are bone marrow transplantation and gene therapy, both of which have significant limitations for widespread use. Individuals with the most severe from of alpha-thalassemia, termed Barts Hydrops Fetalis Syndrome (BHFS), most frequently die during mid-gestation. However, a small number of these patients survive gestation but suffer multiple complications and have life-long transfusion dependence (Songdej et al ., 2017). Both the alpha- and beta-globin loci harbour genes encoding globin chains that are specifically expressed only in the first trimester of gestation (termed embryonic globins) in addition to the genes encoding the adult globin chains that are expressed throughout adult life. The sequential activation and repression of the globin genes throughout development to maturity is termed haemoglobin switching. We are building on our finding that mutations in KLF1 (Viprakasit et al., 2014) derepress zeta-globin to shed light on the regulation of this gene and investigate whether it may be de-repressed in adulthood to ameliorate the symptoms of severe alpha-thalassemia.
It is known that regions of non-coding DNA at linearly remote locations from the genes they regulate (enhancers) can have a profound effect on gene regulation. It has been shown by chromatin conformation capture techniques that gene promoters and enhancers interact in three-dimensional space to boost transcription. However, one limitation of these techniques is that they are performed on whole cell populations.
I am developing a live-cell model in which chromatin at the alpha globin promoter and enhancer sequences is bound by fluorescently labelled proteins. This system will enable us to visualise promoter/enhancer dynamics throughout erythroid differentiation and correlate chromatin movements with gene transcription.
Recapitulation of erythropoiesis in congenital dyserythropoietic anaemia type I (CDA-I) identifies defects in differentiation and nucleolar abnormalities.
Scott C. et al, (2020), Haematologica, Online ahead of print
Publisher Correction: Whole-genome sequencing of a sporadic primary immunodeficiency cohort.
Thaventhiran JED. et al, (2020), Nature, 584
Whole-genome sequencing of a sporadic primary immunodeficiency cohort.
Thaventhiran JED. et al, (2020), Nature, 583, 90 - 95
Whole-genome sequencing of patients with rare diseases in a national health system.
Turro E. et al, (2020), Nature, 583, 96 - 102
Genetic and functional insights into CDA-I prevalence and pathogenesis.
Olijnik A-A. et al, (2020), J Med Genet