Regulation of Chromatin Accessibility by the Farnesoid X Receptor Is Essential for Circadian and Bile Acid Homeostasis In Vivo.
Haider M HassanOladapo OnaboteMajdina IsovicDaniel T PassosFrederick A DickJoseph TorchiaPublished in: Cancers (2022)
The Farnesoid X Receptor (FXR) belongs to the nuclear receptor superfamily and is an essential bile acid (BA) receptor that regulates the expression of genes involved in the metabolism of BAs. FXR protects the liver from BA overload, which is a major etiology of hepatocellular carcinoma. Herein, we investigated the changes in gene expression and chromatin accessibility in hepatocytes by performing RNA-seq in combination with the Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) using a novel FXR knockout mouse model ( Fxr ex5Δ : Nr1h4 ex5Δ/ex5Δ ) generated through CRISPR/Cas9. Consistent with previous Fxr knockout models, we found that Fxr ex5Δ mice develop late-onset HCC associated with increased serum and hepatic BAs. FXR deletion was associated with a dramatic loss of chromatin accessibility, primarily at promoter-associated transcription factor binding sites. Importantly, several genes involved in BA biosynthesis and circadian rhythm were downregulated following loss of FXR, also displayed reduced chromatin accessibility at their promoter regions. Altogether, these findings suggest that FXR helps to maintain a transcriptionally active state by regulating chromatin accessibility through its binding and recruitment of transcription factors and coactivators.
Keyphrases
- long non coding rna
- transcription factor
- gene expression
- poor prognosis
- rna seq
- genome wide
- dna binding
- dna damage
- late onset
- dna methylation
- crispr cas
- single cell
- mouse model
- genome wide identification
- binding protein
- high throughput sequencing
- early onset
- genome editing
- blood pressure
- metabolic syndrome
- oxidative stress
- high throughput
- high fat diet induced