RT Journal Article
SR Electronic
T1 TWIST1 homo- and heterodimers orchestrate specificity control in embryonic stem cell lineage differentiation and craniofacial development
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/2019/06/16/672824.abstract
AB Combinations of bHLH factors dimers generate great functional diversity required for cell type specification in development. The bHLH factor TWIST1 plays pleiotropic roles in craniofacial development. However, which combination of TWIST1 dimers are involved in craniofacial development, and what impact each dimer impose on gene regulation network remained elusive. Proteome profiling of human-TWIST1 expressing cell lines and transcriptome analysis of mouse cranial mesenchyme revealed TWIST1 homodimer and heterodimers with TCF3, TCF4 and TCF12 E-proteins as preferred combinations. We found that balance of homo- and heterodimers were impaired by human disease mutations in TWIST1 Helix domains, which may underpin the developmental defects in haploinsufficiency. Further, loss or gain of function analysis of TWIST1-E-protein dimers in differentiating embryonic stem cells revealed their previously unappreciated roles in lineage specification. TWIST1-E-protein heterodimers activate mesoderm and neural crest differentiation through epithelial-to-mesenchymal transition, whilst TWIST1 homodimers maintained a progenitor-like state and blocked entry to endoderm lineages.