Hematopoietic Stem Cell Biology

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Aim 1. Single cell transcriptional profiling of primitive human hematopoietic cell populations. Aim 2. Comparison of the transcriptional and epigenetic profiles of differentiating mouse hematopoietic cells to the available data in humans gathered as part of ENCODE. In Aim 1, we have determined that transcriptional and epigenetic profiles are determined for mouse megakaryocytic, lymphocytes, neutrophils and monocytes primitive populations of hematopoietic progenitor cells before they have committed to their specific lineages. We have now extended these studies to human hematopoietic stem and progenitor cells. The differentiation of normal human HSPC can be traced at the single cell level by their transcriptional profiles (Roy et al.). In addition, we have shown that the cellular defect in erythroid differentiation in Diamond Blackfan Anemia occurs very early in the process, well before the cells have acquired a distinct erythroid transcription profile. These data have now been deposited in the appropriate databases. This project will terminate on Sept. 30, 2022. In Aim 2, we found that the human MEP population contains three subpopulations of lineage primed cells that could be prospectively separated by surface marker expression. The comparison of the transcriptional and epigenetic profiles of differentiating mouse and human hematopoietic cells is well beyond the capacities of any single lab. Thus we have joined forces with both ENCODE to provide subject expertise and sorted human cells for analysis as well as the ValIdated Systematic IntegratiON of hematopoietic epigenomes consortium (VISION). VISION has focused on the mouse system for several reasons. Mouse and human hematopoiesis, while highly conserved in some respects, also differ in many significant ways. By comparing the mouse and human epigenetic profiles, we will identify overlapping (common) patterns as well as distinct patterns that can be associated with the different properties of mouse and human erythropoiesis, which will generate more informed hypotheses than would be possible by studying hematopoiesis in a single species. For example, haploinsufficiency of ribosomal proteins in humans leads to a block in erythropoiesis resulting in Diamond Blackfan anemia, while haploinsufficiency of ribosomal proteins in mice is benign. We believe that identifying the differences (for example) in mouse and human RP gene regulation may identify a mouse like pathway that could be targeted to treat DBA patients. These data have now been deposited in the appropriate databases. This project will terminate on Sept. 30, 2022.