Abstract:
:MYOD-directed fibroblast trans-differentiation into skeletal muscle provides a unique model to investigate how one transcription factor (TF) reconfigures the three-dimensional chromatin architecture to control gene expression, which is otherwise achieved by the combinatorial activities of multiple TFs. Integrative analysis of genome-wide high-resolution chromatin interactions, MYOD and CTCF DNA-binding profile, and gene expression, revealed that MYOD directs extensive re-wiring of interactions involving cis-regulatory and structural genomic elements, including promoters, enhancers, and insulated neighborhoods (INs). Re-configured INs were hot-spots of differential interactions, whereby MYOD binding to highly constrained sequences at IN boundaries and/or inside INs led to alterations of promoter-enhancer interactions to repress cell-of-origin genes and to activate muscle-specific genes. Functional evidence shows that MYOD-directed re-configuration of chromatin interactions temporally preceded the effect on gene expression and was mediated by direct MYOD-DNA binding. These data illustrate a model whereby a single TF alters multi-loop hubs to drive somatic cell trans-differentiation.
journal_name
Mol Celljournal_title
Molecular cellauthors
Dall'Agnese A,Caputo L,Nicoletti C,di Iulio J,Schmitt A,Gatto S,Diao Y,Ye Z,Forcato M,Perera R,Bicciato S,Telenti A,Ren B,Puri PLdoi
10.1016/j.molcel.2019.07.036subject
Has Abstractpub_date
2019-11-07 00:00:00pages
453-472.e8issue
3eissn
1097-2765issn
1097-4164pii
S1097-2765(19)30591-Xjournal_volume
76pub_type
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