Dynamic Runx1 chromatin boundaries affect gene expression in hematopoietic development.
Dynamic Runx1 chromatin boundaries affect gene expression in hematopoietic development.
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DOI：
10.1038/s41467-022-28376-8
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发表时间：
2022-02-09
影响因子：
16.6
通讯作者：
de Bruijn MFTR
中科院分区：
文献类型：
--
作者：
Owens DDG;Anselmi G;Oudelaar AM;Downes DJ;Cavallo A;Harman JR;Schwessinger R;Bucakci A;Greder L;de Ornellas S;Jeziorska D;Telenius J;Hughes JR;de Bruijn MFTR
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. RUNX1 is a large and complex gene with two alternative promoters and multiple hematopoietic enhancers. Here the authors show that unlike smaller genes Runx1 becomes sub-compartmentalized during differentiation and gene activation. This subcompartmentalization partially depends on CTCF binding at promoter-proximal CTCF sites and transcription.
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影响因子：
16.6
作者：
Bozhilov YK;Downes DJ;Telenius J;Marieke Oudelaar A;Olivier EN;Mountford JC;Hughes JR;Gibbons RJ;Higgs DR
通讯作者：
Higgs DR
影响因子：
4.6
作者：
Fitch, Simon R.;Kapeni, Chrysa;Ottersbach, Katrin
通讯作者：
Ottersbach, Katrin
影响因子：
64.5
作者：
Bonev B;Mendelson Cohen N;Szabo Q;Fritsch L;Papadopoulos GL;Lubling Y;Xu X;Lv X;Hugnot JP;Tanay A;Cavalli G
通讯作者：
Cavalli G
影响因子：
20.3
作者：
Bee, Thomas;Swiers, Gemma;de Bruijn, Marella F. T. R.
通讯作者：
de Bruijn, Marella F. T. R.
影响因子：
5.5
作者：
Bellissimo DC;Speck NA
通讯作者：
Speck NA