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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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, PL

Published Date

  • November 7, 2019

Published In

Volume / Issue

  • 76 / 3

Start / End Page

  • 453 - 472.e8

PubMed ID

  • 31519520

Pubmed Central ID

  • PMC6842445

Electronic International Standard Serial Number (EISSN)

  • 1097-4164

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2019.07.036

Language

  • eng

Conference Location

  • United States