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

ABSTRACT

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.