RT Journal Article
SR Electronic
T1 TWIST1 homodimers and heterodimers orchestrate lineage-specific differentiation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 672824
DO 10.1101/672824
A1 Xiaochen Fan
A1 Ashley J. Waardenberg
A1 Madeleine Demuth
A1 Pierre Osteil
A1 Jane Sun
A1 David A.F. Loebel
A1 Mark Graham
A1 Patrick P.L. Tam
A1 Nicolas Fossat
YR 2019
UL http://biorxiv.org/content/early/2019/12/03/672824.abstract
AB The extensive array of bHLH transcription factors and their combinations as dimers underpin the diversity of molecular function required for cell type specification during embryogenesis. The bHLH factor TWIST1 plays pleiotropic roles during development. However, which combinations of TWIST1 dimers are involved and what impact each dimer imposes on the gene regulation network controlled by TWIST1 remain elusive. In this work, proteomic profiling of human-TWIST1 expressing cell lines and transcriptome analysis of mouse cranial mesenchyme have revealed that TWIST1 homodimer and heterodimers with TCF3, TCF4 and TCF12 E-proteins are the predominant dimer combinations. Dimers formation or their balance are altered by disease-causing mutations in TWIST1 helix domains, which may account for the defective differentiation of the craniofacial mesenchyme observed in patients. Functional analyses of the loss and gain of TWIST1-E-protein dimer activity have revealed previously unappreciated roles in guiding lineage differentiation of embryonic stem cells: TWIST1-E-protein heterodimers activate the differentiation of mesoderm and neural crest cells which is accompanied by epithelial-to-mesenchymal transition, while TWIST1 homodimers maintain the stem cells in a progenitor state and block entry to the endoderm lineage.