RT Journal Article
SR Electronic
T1 The TFIID subunit Taf4 is required for pancreatic beta cell function and identity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.05.23.111898
DO 10.1101/2020.05.23.111898
A1 Thomas Kleiber
A1 Guillaume Davidson
A1 Gabrielle Mengus
A1 Igor Martianov
A1 Irwin Davidson
YR 2020
UL http://biorxiv.org/content/early/2020/08/17/2020.05.23.111898.abstract
AB We selectively inactivated the Taf4 subunit of general transcription factor TFIID in adult murine pancreatic beta cells (BCs). Taf4 inactivation rapidly diminishes expression of critical genes involved in BC function leading to increased glycaemia, lowered plasma insulin levels, defective glucose-stimulated insulin secretion and in the longer term reduced BC mass through apoptosis of a subpopulation of BCs. Nevertheless, glycaemia and blood insulin levels are stabilised after 11 weeks with mutant animals showing long term survival. Bulk RNA-seq and ATAC-seq together with single cell RNA-seq on isolated Langerhans islets show that Taf4 loss leads to a remodelling of chromatin accessibility and gene expression not only in targeted BCs, but also alpha and delta cells. One week after Taf4-loss, cells with mixed BC, alpha and/or delta cell identities were observed as well as a BC population trans-differentiating into alpha-like cells. Computational analysis defines how known critical BC and alpha cell determinants may act in combination with additional transcription factors and the NuRF chromatin remodelling complex to promote BC trans-differentiation.Competing Interest StatementThe authors have declared no competing interest.