Transcription Factor-Directed Re-wiring of Chromatin Architecture for Somatic Cell Nuclear Reprogramming toward trans-Differentiation

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. [Display omitted] •MYOD drives the re-wiring of chromatin interactions during trans-differentiation•MYOD alters chromatin interactions between cis-regulatory elements•MYOD re-wires insulated neighborhoods, hotspots of differential interactions•MYOD re-wiring of chromatin interactions temporally precedes transcriptional changes Dall’Agnese et al. find that the myogenic master transcription factor MYOD drives significant re-wiring of the 3D chromatin architecture during somatic reprogramming toward transdifferentiation, in order to erase the cell-of-origin transcriptional program and activate skeletal myogenesis. MYOD-directed reconfiguration of chromatin interactions involves cis-regulatory and structural genomic elements and temporally precedes transcriptional regulation of target genes.