Dynamic Runx1 chromatin boundaries affect gene expression in hematopoietic development

Dominic D. G. Owens, Giorgio Anselmi, A. Marieke Oudelaar, Damien J. Downes, Alessandro Cavallo, Joe R. Harman, Ron Schwessinger, Akin Bucakci, Lucas Greder, Sara Ornellas, Danuta Jeziorska, Jelena Telenius, Jim R. Hughes () and Marella F. T. R. Bruijn ()
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Dominic D. G. Owens: University of Oxford
Giorgio Anselmi: University of Oxford
A. Marieke Oudelaar: University of Oxford
Damien J. Downes: University of Oxford
Alessandro Cavallo: University of Oxford
Joe R. Harman: University of Oxford
Ron Schwessinger: University of Oxford
Akin Bucakci: University of Oxford
Lucas Greder: University of Oxford
Sara Ornellas: University of Oxford
Danuta Jeziorska: University of Oxford
Jelena Telenius: University of Oxford
Jim R. Hughes: University of Oxford
Marella F. T. R. Bruijn: University of Oxford

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract The transcription factor RUNX1 is a critical regulator of developmental hematopoiesis and is frequently disrupted in leukemia. Runx1 is a large, complex gene that is expressed from two alternative promoters under the spatiotemporal control of multiple hematopoietic enhancers. To dissect the dynamic regulation of Runx1 in hematopoietic development, we analyzed its three-dimensional chromatin conformation in mouse embryonic stem cell (ESC) differentiation cultures. Runx1 resides in a 1.1 Mb topologically associating domain (TAD) demarcated by convergent CTCF motifs. As ESCs differentiate to mesoderm, chromatin accessibility, Runx1 enhancer-promoter (E-P) interactions, and CTCF-CTCF interactions increase in the TAD, along with initiation of Runx1 expression from the P2 promoter. Differentiation to hematopoietic progenitor cells is associated with the formation of tissue-specific sub-TADs over Runx1, a shift in E-P interactions, P1 promoter demethylation, and robust expression from both Runx1 promoters. Deletion of promoter-proximal CTCF sites at the sub-TAD boundaries has no obvious effects on E-P interactions but leads to partial loss of domain structure, mildly affects gene expression, and delays hematopoietic development. Together, our analysis of gene regulation at a large multi-promoter developmental gene reveals that dynamic sub-TAD chromatin boundaries play a role in establishing TAD structure and coordinated gene expression.

Date: 2022
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DOI: 10.1038/s41467-022-28376-8

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