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.

中文翻译：

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TFIID亚基Taf4是胰腺β细胞功能和特性所必需的。

我们选择性地灭活了成年鼠胰腺β细胞（BCs）中一般转录因子TFIID的Taf4亚基。Taf4失活会迅速减少与BC功能有关的关键基因的表达，从而导致血糖​​升高，血浆胰岛素水平降低，葡萄糖刺激的胰岛素分泌不良，并且从长远来看会通过BCs亚群的凋亡降低BC质量。尽管如此，突变动物表现出长期存活后，血糖和血液胰岛素水平在11周后稳定下来。散装的Langerhans胰岛上的散装RNA-seq和ATAC-seq以及单细胞RNA-seq显示，Taf4丢失不仅导致靶向BCs，而且还导致α和δ细胞的染色质可及性和基因表达发生重塑。Taf4丢失后一周，混合BC的细胞，观察到α和/或δ细胞身份以及BC细胞群转分化为α样细胞。计算分析定义了已知的关键BC和alpha细胞决定簇如何与其他转录因子和NuRF染色质重塑复合物结合以促进BC转分化。