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.

doi:10.1101/2023.04.18.537282

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bioRxiv · 10.1101/2023.04.18.537282

Cell Type-Specific Regulation by a Heptad of Transcription Factors in Human Hematopoietic Stem and Progenitor Cells

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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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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.. 2023-04-18. Cell Type-Specific Regulation by a Heptad of Transcription Factors in Human Hematopoietic Stem and Progenitor Cells. https://doi.org/10.1101/2023.04.18.537282

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