Aug 2026· The FASEB Journal· Vol 40 15, pp.
e72171
· 0 citations· 73 references
Medicine
TL;DR
The SIRT1 exon 2-encoded IDR is identified as a non-catalytic regulatory element that contributes to the timing of hepatic transcriptional responses during nutrient stress and impair fasting adaptation and glucose homeostasis.
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 SIRT1ΔE2 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.
Summary Amino acid catabolism during fasting requires coordinated nitrogen disposal and glucose production, but the transcriptional logic linking the urea cycle to gluconeogenesis remains unclear. Forkhead box O (FoxO) transcription factors regulate fasting metabolism, and here we identify FoxOs as direct hepatic regulators of argininosuccinate synthase 1 (Ass1). Acute hepatic FoxO1/3a knockdown in fasted mice reduced Ass1 expression, lowered blood glucose, and altered urea-cycle amino acids, with decreased arginine and increased ornithine, even in Klf15-deficient livers. Ass1 silencing phenocopied these effects and impaired glucose production from pyruvate and lactate, whereas Ass1 overexpression restored glucose production in FoxO-inhibited hepatocytes. Mechanistically, we identified a functional FoxO-binding element within an upstream Ass1 enhancer and confirmed its fasting-inducible activity by reporter assays, electrophoretic mobility shift assays, in vivo imaging, and chromatin immunoprecipitation. These findings establish a KLF15-independent FoxO-Ass1 axis that coordinates ureagenesis with gluconeogenesis during fasting and supports hepatic metabolic adaptation to nutrient deprivation.
S. Karkoutly, Yoshinori Takeuchi, Zahra Mehrazad Saber et al.· iScience· 0 citations
GCN2 is established as a major sensor mediating the early hepatic response to SAA deprivation, and a transcriptional program essential for maintaining amino acid homeostasis is defined, highlighting a coordinated adaptive response to acute SAA deprivation.
Valérie Carraro, M. Cherpaz, L. Longechamp et al.· Journal of Molecular Biology· 0 citations
AIMS
Heart failure is marked by suppression of fatty acid oxidation (FAO) and mitochondrial ATP production gene expression. While transcriptional downregulation via PGC-1 and PPARα/ERRα has been well documented, the involvement of the general transcriptional machinery remains insufficiently understood. Distinct from its salutary role in many cardiac conditions, endogenous Sirt1 negatively affects cardiac function during pressure overload (PO). This study investigates how Sirt1 modulates preinitiation complex (PIC) assembly and RNA polymerase II (Pol II) recruitment during pathological PO.
METHODS AND RESULTS
Cardiac-specific Sirt1 knock-out (Sirt1 cKO) mice were subjected to PO. Interaction between Sirt1 and Sub1, a protein recruiting GTFs to the gene promoter, was assessed with co-immunoprecipitation, protein pull-down and molecular docking. Pol II recruitment was evaluated with ChIP-sequencing and -qPCR analyses. The binding affinity of Sirt1 and GTF to the Sub1 GTF binding domain was assessed by immunoprecipitation and protein pull-down assays. Unbiased ChIP-sequencing and -qPCR analyses showed that Pol II binding to metabolic gene promoters was downregulated during PO, which was reversed in Sirt1 cKO mice. PO upregulated Sirt1 in the heart and increased its binding to Sub1, which interacts PPARα and ERRα, but not NF-kB. The Sirt1 binding to Sub1 competitively displaced the interaction between Sub1 and GTFs, thereby inhibiting the PIC formation at the Sub1-PPARα/ERRα complex.
CONCLUSIONS
Sirt1 impairs metabolic gene transcription during PO by competitively inhibiting Sub1-mediated recruitment of GTFs and PIC formation. This repression of general transcriptional machinery contributes to the metabolic disturbance and may represent a maladaptive component of the heart failure phenotype.
Retinol binding protein 4 (RBP4) exhibits diurnal oscillatory pattern and is elevated under conditions of circadian disruption and in type 2 diabetes mellitus, yet the molecular link between RBP4 and impaired glucose metabolism remains elusive. Here, we overexpressed RBP4 in human hepatoma Huh7 cells and performed integrated RNA sequencing (RNA-seq), Co-immunoprecipitation (Co-IP) coupled with mass spectrometry (MS), and Cleavage Under Targets and Tagmentation (CUT&Tag). We identified BACH1 as a direct RBP4□interacting transcription factor that predominantly binds the TGACTCA motif in promoter regions of genes involved in carbon metabolism pathways. Integrative analysis of RNA seq and CUT&Tag data uncovered 63 direct target genes co regulated by RBP4 and BACH1, including known circadian and metabolic regulators SLC7A11, PFKFB3, CTCF, NR1D2 and WEE1 as well as novel candidates SF1 and PIN1. These target genes are significantly enriched in insulin receptor signaling and carbohydrate metabolic pathways. Mechanistically, the RBP4–BACH1 axis reprograms glucose metabolism, linking circadian rhythm disturbances to dysregulated glucose homeostasis. Collectively, our findings establish a functional role for RBP4 in connecting circadian disruption to diabetes and highlight RBP4 as a potential therapeutic target.
Li Wang, Qi Ma, Yao Chen et al.· bioRxiv· 0 citations
Fasting is an effective physiological intervention eliciting global and cellular adaptations that can improve healthspan and lifespan. In addition to its metabolic effects, fasting is a state of modulation of aging-associated processes/adaptive cellular responses that drives an intense epigenomic and transcriptional remodeling response which preserves functional capacity during aging. Nutrient deprivation elicits the activation of evolutionarily conserved nutrient-sensing pathways including AMPK and sirtuins, which can modulate chromatin accessibility and transcriptomic programs. These changes impact critical epigenetic processes like histone modifications, DNA methylation, and non-coding RNAs which underline adaptive transcriptional programs that drive cellular maintenance, autophagy, and stem cell function. Recent studies also suggest that fasting-mediated epigenomic flexibility may help reduce age-related epigenetic drift, dampen chronic inflammation, and cellular adaptation/maintenance of cellular function across various tissues. Notably, these processes may link fasting to both lifespan and age-related disease resistance, including metabolic disorders, neurodegeneration, and cancer. This review aims to synthesize current knowledge on how fasting modulates epigenomic landscapes/influences epigenomic regulation and transcriptome to impact aging and healthspan. We highlight key molecular pathways, cell-type specific effects, and emerging translational opportunities, while also discussing challenges, limitations, and open questions that need to be addressed to leverage fasting-inspired approaches for healthspan to promote healthy aging.
A. Harrath, M. Jalouli, Md. Ataur Rahman et al.· Mechanisms of Ageing and Dev...· 0 citations
Summary Post-transcriptional gene regulation is central to maintaining cellular homeostasis. Among its mechanisms, alternative splicing (AS) fine-tunes cellular adaptation to stress. This study employed an approach combining RNA splicing analysis with RNA-binding protein (RBP) motif enrichment in primary osteocytes cultured in high-glucose conditions. Our analysis identified the RBP human antigen R (HuR) as a top candidate associated with AS regulation. Loss of HuR reshaped the transcriptome through gene expression and splicing changes, converging on two major pathways: stress response and translational control. Functional validation revealed that HuR depletion heightened oxidative stress, impaired mitochondrial function, and rewired key translational signals, while preserving global protein output. Mechanistically, we identified TXNIP mRNA-protein uncoupling following HuR knockdown (KD), characterized by elevated mRNA but reduced protein expression. Collectively, these findings support HuR’s role as a key post-transcriptional regulator of osteocyte metabolic adaptation under high-glucose stress, with potential implications for hyperglycemic bone fragility.
Z. Fan, A. Marahleh, H. Kitaura et al.· iScience· 0 citations
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