Genome-wide analysis of FoxO1 binding in hepatic chromatin: Potential involvement of FoxO1 in linking retinoid signaling to hepatic gluconeogenesis

Abstract

The forkhead transcription factor FoxO1 is a critical regulator of hepatic glucose and lipid metabolism, and dysregulation of FoxO1 function has been implicated in diabetes and insulin resistance. We globally identified FoxO1 occupancy in mouse hepatic chromatin on a genome-wide level by chromatin immunoprecipitation coupled with high-throughput DNA sequencing (ChIP-seq). To establish the specific functional significance of FoxO1 against other FoxO proteins, ChIP-seq was performed with chromatin from liver-specific FoxO1 knockout and wild-type mice. Here we identified 401 genome-wide FoxO1-binding locations. Motif search reveals a sequence element, 5′ GTAAACA 3′, consistent with a previously known FoxO1-binding site. Gene set enrichment analysis shows that the data from FoxO1 ChIP-seq are highly correlated with the global expression profiling of genes regulated by FoxO1, demonstrating the functional relevance of our FoxO1 ChIP-seq study. Interestingly, gene ontology analysis reveals the functional significance of FoxO1 in retinoid metabolic processes. We show here that FoxO1 directly binds to the genomic sites for the genes in retinoid metabolism. Notably, deletion of FoxO1 caused a significantly reduced induction of Pck1 and Pdk4 in response to retinoids. As Pck1 and Pdk4 are downstream targets of retinoid signaling, these results suggest that FoxO1 plays a potential role in linking retinoid metabolism to hepatic gluconeogenesis.

Intermittent glucocorticoid steroid dosing enhances muscle repair without eliciting muscle atrophy

“…25) were (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/JCI91445DS1).…”

Loss of Interdependent Binding by the FoxO1 and FoxA1/A2 Forkhead Transcription Factors Culminates in Perturbation of Active Chromatin Marks and Binding of Transcriptional Regulators at Insulin-sensitive Genes

“…Comparison of ChIP-sequencing results for FoxO1 and FoxA2 in adult mouse liver has recently revealed that FoxO1 and FoxA2 co-target multiple genes linked to metabolic pathways for glucose, carboxylic acids, lipids, and steroids in liver (73). Therefore, interdependent FoxO1-FoxA1/A2 binding revealed for the IGFPB1 and G6Pase promoters probably represents a general regulatory mechanism enabling modulation of active chromatin states in response to extracellular cues for a broad array of hepatic metabolic processes.…”

H2A.B facilitates transcription elongation at methylated CpG loci

“…Instead, several other histone variants, such as H2A.Z and H3.3, as well as specific histone modifications, are enriched at TSSs, which facilitates transcription initiation (Schwartz and Ahmad 2005;Anamika et al 2010;Wang et al 2013). In contrast, DNA methylation at the TSS is associated with transcription suppression because DNA methylation is likely to set the TSS in a compact stage to abrogate transcription initiation (Ehrlich et al 1982;Shin et al 2012;Wang et al 2013).…”