SIRT1 Exon 2-Encoded IDR Gates CREB-Dependent Transcriptional Timing During Fasting

Metabolic adaptation to fasting requires precise temporal control of gene expression. Although transcription factors and upstream co-regulators that mediate the fasting response are well studied, the role of intrinsically disordered regions in coordinating transcriptional timing remains unclear. Here, we identify the exon 2-encoded intrinsically disordered region of SIRT1 as a regulator of fasting-responsive transcription in the liver. Using a physiological SIRT1^ΔE2 mouse model, we show that loss of this region alters the sequence and magnitude of starvation-induced transcriptional responses, leading to premature activation of gluconeogenic genes and excessive hepatic glucose output. Mechanistically, exon 2 loss weakens SIRT1 interaction with CREB and reduces the ability of SIRT1 to restrain CREB-dependent transcription, while also affecting interactions with FOXO1 and PPARα. These changes impair fasting adaptation and glucose homeostasis. Together, our findings identify the SIRT1 exon 2-encoded IDR as a non-catalytic regulatory element that contributes to the timing of hepatic transcriptional responses during nutrient stress.