Cell Type-Specific Regulation by a Heptad of Transcription Factors in Human Hematopoietic Stem and Progenitor Cells
Subramanian, S.; Thoms, J.; Huang, Y.; Cornejo, P.; Koch, F. C.; Jacquelin, S.; Shen, S.; Song, E.; Joshi, S.; Brownlee, C.; Woll, P. S.; Fajardo, D. C.; Beck, D.; Curtis, D. J.; Yehson, K.; Antonenas, V.; O'Brien, T.; Trickett, A.; Powell, J. A.; Lewis, I. D.; Pitson, S. M.; Gandhi, M. K.; Lane, S. W.; Vafaee, F.; Wong, E.; Gottgens, B.; Rokny, H. A.; Wong, J. W. H.; Pimanda, J. E.
Show abstract
Hematopoietic stem and progenitor cells (HSPCs) rely on a complex interplay of transcription factors (TFs) to regulate differentiation into mature blood cells. A heptad of TFs - FLI1, ERG, GATA2, RUNX1, TAL1, LYL1, LMO2 - bind regulatory elements in bulk CD34+ HSPCs. However, whether specific heptad-TF combinations have distinct roles in regulating hematopoietic differentiation remained unknown. We mapped genome-wide chromatin contacts and TF binding profiles in HSPC subsets (HSC, CMP, GMP, MEP) and found that heptad occupancy and enhancer-promoter interactions varied significantly across cell types and were associated with cell-type-specific gene expression. Distinct regulatory elements were enriched with specific heptad-TF combinations, including stem-cell-specific elements with ERG, and myeloid- and erythroid-specific elements with combinations of FLI1, RUNX1, GATA2, TAL1, LYL1, and LMO2. These findings suggest that specific heptad-TF combinations play critical roles in regulating hematopoietic differentiation and provide a valuable resource for development of targeted therapies to manipulate specific HSPC subsets.
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