Dynamic Runx1 chromatin boundaries affect gene expression in hematopoietic development.

Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE

Original Publication: [London] : Nature Pub. Group

Gene Expression*; Chromatin/*metabolism ; Core Binding Factor Alpha 2 Subunit/*genetics ; Core Binding Factor Alpha 2 Subunit/*metabolism; Animals ; Cell Cycle Proteins/metabolism ; Cell Differentiation ; DNA/chemistry ; Gene Expression Regulation, Developmental ; Hematopoietic Stem Cells/metabolism ; Mesoderm/metabolism ; Mice ; Nucleic Acid Conformation ; Promoter Regions, Genetic

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.
(© 2022. The Author(s).)

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G0902418 United Kingdom MRC_ Medical Research Council; 105281/Z/14/Z United Kingdom WT_ Wellcome Trust; MR/X001210/1 United Kingdom MRC_ Medical Research Council; 108870/Z/15/Z United Kingdom WT_ Wellcome Trust; 106130/Z/14/Z United Kingdom WT_ Wellcome Trust; MC_UU_00029/3 United Kingdom MRC_ Medical Research Council; United Kingdom WT_ Wellcome Trust; MC_UU_00016/14 United Kingdom MRC_ Medical Research Council; MR/T014067/1 United Kingdom MRC_ Medical Research Council; MC_UU_00016/2 United Kingdom MRC_ Medical Research Council; 203728/Z/16/Z United Kingdom WT_ Wellcome Trust; MC_UU_12009/2 United Kingdom MRC_ Medical Research Council; MR/N00969X/1 United Kingdom MRC_ Medical Research Council; MR/K015777X/1 United Kingdom MRC_ Medical Research Council

0 (Cell Cycle Proteins)
0 (Chromatin)
0 (Core Binding Factor Alpha 2 Subunit)
0 (Runx1 protein, mouse)
9007-49-2 (DNA)

Date Created: 20220210 Date Completed: 20220307 Latest Revision: 20240313

20240313

PMC8828719

10.1038/s41467-022-28376-8

35140205