Abstract
Regulation of gene expression involves a complex and dynamic dialogue between transcription factors, chromatin remodelling and modification complexes and the basal transcription machinery. To address the function of the Taf4 subunit of general transcription factor TFIID in the regulation of insulin signalling, it was inactivated in adult murine pancreatic beta cells. Taf4 inactivation impacted the expression of critical genes involved in beta-cell function leading to increased glycaemia, lowered plasma insulin levels and defective glucose-stimulated insulin secretion. One week after Taf4-loss, single-cell RNA-seq revealed cells with mixed beta cell, alpha and/or delta cell identities as well as a beta cell population trans-differentiating into alpha-like cells. Computational analysis of single-cell RNA-seq defines how known critical beta cell and alpha cell determinants may act in combination with additional transcription factors and the NuRF chromatin remodelling complex to promote beta cell trans-differentiation.
Highlights
Pancreatic Langerhans islets comprise multiple hormone-secreting cell types that cooperate to regulate glucose homeostasis in the organism
Taf4 is essential for normal beta-cell function Taf4 inactivation in adult murine beta cells led to increased glycaemia due to defective insulin signalling and secretion, a consequence of an immediate and major impact on gene expression
At 34 weeks, Taf4expressing beta cells were again detected, but their proportion did not increase by 55 weeks
Summary
Pancreatic Langerhans islets comprise multiple hormone-secreting cell types that cooperate to regulate glucose homeostasis in the organism. Alpha cells have a plastic epigenetic state with many loci showing bivalent chromatin modifications [7] and can be converted to beta-like insulin-secreting cells by overexpression of beta cell-determining factors [8] or loss of Arx and Dnmt1 [9]. Regulation of gene expression requires a dynamic dialogue between transcription factors binding cis-regulatory elements, chromatin remodelling and modification complexes and the basal transcription machinery [16,17,18,19,20]. Basal transcription factor TFIID comprising the TATA-box binding protein (TBP) and 13–14 TBP-associated factors (TAFs) plays a critical role in this communication and in pre-initiation complex (PIC) formation [21, 22]. In lobe B, the conserved TAF4 C-terminal domain contacts promoter DNA and the TFIIATBP module suggesting they promote TBP DNA binding and fix the distance between the TBP binding and the transcription start sites
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