Control of Telomere Homeostasis by Nucleotide Metabolism in Hematopoiesis

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PROJECT SUMMARY/ABSTRACT: Telomere homeostasis is critical for cellular replicative capacity and human health. Telomeres shorten with cellular replication and when critically short, trigger senescence and halt cell division. Inherited mutations in telomere maintenance genes are associated with severe hematopoietic disorders including childhood-onset bone marrow failure, aplastic anemia, and myelodysplastic syndrome, as well as non-hematopoietic conditions including liver cirrhosis and pulmonary fibrosis. These diseases are collectively referred to as telomere biology disorders (TBDs). Treatment for TBDs is centered on supportive care and bone marrow or organ transplant which often have poor outcomes and leave patients at risk for other disease manifestations. New approaches to therapeutically lengthen telomeres and treat TBDs are needed. In order to identify novel pathways controlling human telomere length, we recently performed a genome-wide CRISPR/Cas9 screen with a telomere length readout. In addition to identifying known telomere maintenance genes, we identified an association between several nucleotide metabolism genes and telomere length. Recent human genome wide association studies have also connected nucleotide metabolism genes and telomere length in blood cells. Preliminary experiments performed in our laboratory demonstrate that both genetic and small molecule perturbations of nucleotide metabolism can rapidly and robustly alter telomere length in human cells, including induced pluripotent stem cells derived from patients with TBDs. However, there are fundamental knowledge gaps both in the mechanisms underlying this effect, and whether manipulating nucleotide metabolism could alter telomere maintenance in the hematopoietic system, which could be therapeutically useful. Here, we aim to uncover how nucleotide metabolism perturbations alter telomere length in human cells, including in vitro and in vivo models of human hematopoiesis. This study consists of two aims to investigate: (1) how altering nucleotide metabolism genes impacts telomere maintenance, and (2) how small molecule manipulation of nucleotide metabolism alters telomere homeostasis, in human cells including primary hematopoietic stem and progenitor cells. For this F30 award, the PI has designed a research strategy and training program that will provide him with: (1) fundamental expertise in metabolomics, bioinformatics, and telomere biology, (2) an expert group of mentors and collaborators to promote not only research expertise, but also career-long academic skills including grantsmanship and scientific communication, and (3) experience performing translation-focused hematology research in preparation for his career goal as a physician-scientist. This proposal will take place in the rich and collaborative Harvard Medical School and Boston Children’s Hospital research environments. Completion of this work is expected to establish nucleotide metabolism as a critical regulator of human telomere homeostasis, with therapeutic implications for the treatment of hematopoietic diseases with high unmet need including bone marrow failure and aplastic anemia, as well as other non-hematopoietic degenerative diseases.