Biology subjects

Bochkis, I.

Publications and source records attributed to Bochkis, I..

4 recordsLinked to original sources

bioRxiv2024

Reduced ZMPSTE24 expression leads to prelamin accumulation and development of steatosis in MASLD patients.

Mutations of nuclear lamina-associated proteins LMNA and ZMPSTE24 have been associated with fatty liver. We report that the changes at the nuclear envelope we described in MASLD patients are caused by downregulation of ZMPSTE24, an enzyme that processes prelamin to mature lamin A. In addition, Zmpste24 mutant mice develop hepatic steatosis and exhibit upregulation of p53 target genes. p53 activity is also induced in genes differentially expressed in MASLD patients. Furthermore, p53 regulates genes bound by FOXA2 in these individuals, corresponding to observations in Zmpste24 mutants. In contrast, expression of glucose and insulin regulated genes is reduced in MASLD patients, suggesting altered glucose metabolism and insulin resistance, hallmarks of type 2 diabetes (T2D). Hence, our genomics data show that MASLD patients with severe steatosis but yet without MASH are already suffering from severe metabolic consequences and underscore the need for treatment at this stage of the disease.

physiology↗

bioRxiv2023

Pioneer factor Foxa2 mediates chromatin conformation changes in ligand-dependent activation of nuclear receptor FXR

ABSTACTActivation of nuclear receptors, a family of ligand-dependent transcription factors, is used extensively in development of drug targets. We have previously shown that pioneer factor Foxa2 opens chromatin for binding of nuclear receptors FXR and LXR during acute ligand activation. FXR is activated by bile acids and deletion of Foxa2 in the liver results in intrahepatic cholestasis. We hypothesized that Foxa2 also enables chromatin conformational changes during ligand activation. We performed Foxa2 HiChIP to assess Foxa2-dependent long-range interactions in mouse livers treated with either vehicle control or FXR agonist GW4064. HiChIP contact analysis shows that global chromatin interactions are dramatically increased during FXR activation. Ligand-treated livers exhibit extensive redistribution of topological associated domains (TAD and substantial increase in Foxa2-anchored loops, suggesting Foxa2 is involved in dynamic chromatin conformational changes. We demonstrate that chromatin conformation, including genome-wide interactions, TADs, intra-chromosomal and inter-chromosomal Foxa2-anchored loops, drastically changes upon addition of FXR agonist. Hence, we determine a novel role for Foxa2 in enabling these conformational changes, extending its function in bile acid metabolism.

pharmacology and toxicology↗

bioRxiv2022

Feeding desensitizes A1 adenosine receptors in adipose through FOXO1-mediated transcriptional regulation

Adipose tissue is a critical regulator of energy balance that must rapidly shift its metabolism between fasting and feeding to maintain homeostasis. Adenosine has been characterized as an important regulator of adipocyte metabolism primarily through its actions on A1 adenosine receptors (A1R). We sought to understand the role A1R plays in adipocytes during fasting and feeding to regulate glucose and lipid metabolism by using an inducible, adiponectin-Cre with Adora1 floxed mice (FAdora1-/-), where F designates a fat-specific deletion. Fadora1-/- mice had impairments in the suppression of lipolysis by insulin on normal chow and impaired glucose tolerance on high-fat diet. FAdora1-/- mice also exhibited a higher lipolytic response to isoproterenol than WT controls when fasted, but not after a 4-hour refeeding period. We found that FOXO1 binds to the A1R promoter in adipocytes. Upon feeding, signaling along the insulin-Akt-FOXO1 axis leads to a rapid downregulation of A1R transcript and desensitization of adipocytes to A1R agonism. Obesity also desensitizes adipocyte A1R, and this is accompanied by a disruption of cyclical changes in A1R transcription between fasting and refeeding. We propose that FOXO1 drives high A1R expression under fasted conditions to limit excess lipolysis during stress and augment insulin action upon feeding. Subsequent downregulation of A1R under fed conditions facilitates reentrance into the catabolic state upon fasting.

physiology↗

bioRxiv2020

Pioneer factor Foxa2 enables ligand-dependent activation of LXRα

Type II nuclear hormone receptors, such as FXR, LXR, and PPAR, which function in glucose and lipid metabolism and serve as drug targets for metabolic diseases, are permanently positioned in the nucleus regardless of the ligand status. Ligand activation of these receptors is thought to occur by co-repressor/co-activator exchange, followed by initiation of transcription. However, recent genome-wide location analysis showed that LXR and PPAR binding in the liver is largely ligand-dependent. We hypothesized that pioneer factor Foxa2 evicts nucleosomes to enable ligand-dependent receptor binding. We show that chromatin accessibility, LXR occupancy, and LXR-dependent gene expression upon ligand activation require Foxa2. Unexpectedly, Foxa2 occupancy is drastically increased when LXR is bound by an agonist. Our results suggest that Foxa2 and LXR bind DNA as an interdependent complex during ligand activation. Our model requiring pioneering activity for ligand activation challenges the existing co-factor exchange mechanism and expands current understanding of nuclear receptor biology, suggesting that chromatin accessibility needs to be considered in design of drugs targeting nuclear receptors.

genetics↗