Humans vary considerably in the process of red blood cell production (erythropoiesis). Such variation contributes to diseases, including numerous forms of anemia. Much of this variation is attributable to genetic polymorphisms found in the population. However, as with most other complex diseases and traits, how such variation impacts the process of erythropoiesis remains poorly understood. We have made tremendous progress in beginning to decipher how human genetic variation impacts erythropoiesis during the first five years of this grant from the NIDDK. We have pioneered the use of massively parallel reporter assays as an approach to systematically dissect how non-coding genetic variation revealed from genome-wide association studies (GWAS) functionally impacts transcriptional regulatory elements. We have also utilized CRISPR/Cas9 genome editing to bolster these findings in an endogenous context. In this competitive renewal application, we aim to invigorate these studies and directly address how human genetic variation shapes the non-coding genomic landscape of erythropoiesis. We will build upon our prior studies and use innovative new approaches to ask these questions in primary human erythroid cells. We have recently conducted one of the largest GWAS of erythroid traits and have identified over 1,800 distinct associated loci. We propose to utilize a number of cutting-edge genomic tools that will allow us to gain important insights from these emerging large-scale genetic studies. First, we aim to define putative causal variants underlying these associations and their functional effects on the linked transcriptional regulatory elements. Second, we will systematically identify target genes that may be affected by the regulatory elements harboring trait-associated variation. Finally, we will dissect mechanisms of action by which a subset of these variants impact target genes and alter human erythropoiesis. Not only will the proposed studies over the next five years significantly advance our understanding of human erythropoiesis and related diseases, but this work will also serve as a paradigm for the systematic dissection of other complex diseases and traits.

Public Health Relevance

Red blood cell production is frequently impaired in human diseases and displays considerable variation among individuals. This grant renewal application builds upon our prior studies of how genetic factors contribute to such variation in health and disease. We propose to gain a deeper understanding of the mechanisms by which such genetic variation can impact gene expression and the process of red blood cell production, with the ultimate goal of being able to develop better treatments for human diseases affecting this process.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Bishop, Terry Rogers
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Boston Children's Hospital
United States
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Kim, Ah Ram; Sankaran, Vijay G (2018) Thrombopoietin: tickling the HSC's fancy. EMBO Mol Med 10:10-12
Khajuria, Rajiv K; Munschauer, Mathias; Ulirsch, Jacob C et al. (2018) Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis. Cell 173:90-103.e19
Guo, Michael H; Nandakumar, Satish K; Ulirsch, Jacob C et al. (2017) Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms. Proc Natl Acad Sci U S A 114:E327-E336
Fiorini, Claudia; Abdulhay, Nour J; McFarland, Sean K et al. (2017) Developmentally-faithful and effective human erythropoiesis in immunodeficient and Kit mutant mice. Am J Hematol 92:E513-E519
Kim, Ah Ram; Ulirsch, Jacob C; Wilmes, Stephan et al. (2017) Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation. Cell 168:1053-1064.e15
Kim, Ah Ram; Sankaran, Vijay G (2016) Development of autologous blood cell therapies. Exp Hematol 44:887-94
Polfus, Linda M; Khajuria, Rajiv K; Schick, Ursula M et al. (2016) Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis. Am J Hum Genet 99:481-8
Wakabayashi, Aoi; Ulirsch, Jacob C; Ludwig, Leif S et al. (2016) Insight into GATA1 transcriptional activity through interrogation of cis elements disrupted in human erythroid disorders. Proc Natl Acad Sci U S A 113:4434-9
Ulirsch, Jacob C; Nandakumar, Satish K; Wang, Li et al. (2016) Systematic Functional Dissection of Common Genetic Variation Affecting Red Blood Cell Traits. Cell 165:1530-1545
Giani, Felix C; Fiorini, Claudia; Wakabayashi, Aoi et al. (2016) Targeted Application of Human Genetic Variation Can Improve Red Blood Cell Production from Stem Cells. Cell Stem Cell 18:73-78

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