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

Area of Science:

• Metabolic regulation
• Molecular biology
• Gene expression control

Background:

• Metabolic adaptation to fasting depends on precise gene expression timing.
• The role of intrinsically disordered regions (IDRs) in coordinating transcriptional timing during fasting is not well understood.
• Key transcription factors and co-regulators of the fasting response are known, but regulatory elements like IDRs are less explored.

Purpose of the Study:

• To investigate the role of the intrinsically disordered region (IDR) encoded by exon 2 of SIRT1 in regulating fasting-responsive transcription in the liver.
• To elucidate the molecular mechanisms by which the SIRT1 exon 2 IDR influences hepatic gene expression during nutrient stress.
• To determine the impact of the SIRT1 exon 2 IDR on fasting adaptation and glucose homeostasis.

Main Methods:

• Development and utilization of a physiological SIRT1ΔE2 mouse model lacking the exon 2-encoded IDR.
• Analysis of starvation-induced transcriptional responses in the liver of wild-type and SIRT1ΔE2 mice.
• Investigation of SIRT1 interactions with key transcription factors, including CREB, FOXO1, and PPARα.

Main Results:

• Loss of the SIRT1 exon 2 IDR alters the sequence and magnitude of starvation-induced transcriptional changes in the liver.
• Premature activation of gluconeogenic genes and excessive hepatic glucose output were observed in SIRT1ΔE2 mice.
• Exon 2 deletion weakened SIRT1 interaction with CREB, reducing its ability to restrain CREB-dependent transcription, and affected interactions with FOXO1 and PPARα.

Conclusions:

• The SIRT1 exon 2-encoded IDR acts as a critical non-catalytic regulatory element.
• This IDR contributes to the precise timing of hepatic transcriptional responses during nutrient stress (fasting).
• Dysregulation of the SIRT1 exon 2 IDR impairs fasting adaptation and glucose homeostasis.