A hierarchical regulatory network ensures stable albumin transcription under various pathophysiological conditions
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ABSTRACT:
PROVIDER: PRJNA751052 | ENA |
REPOSITORIES: ENA
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Project description:Physiologically, albumin is produced by hepatocytes. It remains largely unknown how patients are capable of maintaining essential albumin levels even in the condition of liver failure. Here, we delineate a hierarchical regulatory network that controls albumin transcription under different pathophysiological conditions. The ALB core promoter possesses a TATA box and nucleosome-free area, which allows constitutive binding of RNA Pol II and thus initiation of transcription. In normal conditions, HNF4α and C/EBPα facilitate albumin transcription through binding to its promoter. In severely damaged livers, hepatocellular HNF4α and C/EBPα expression is often inhibited. The absence of HNF4 and C/EBPα increases hedgehog ligand biosynthesis. Hedgehog upregulates FOXA2 expression through transcription factor GLI2 binding to the FOXA2 promoter. Subsequently, FOXA2 maintains albumin expression in the hepatocytes lacking HNF4α and C/EBPα. In patients with massive hepatocyte loss, the expression of albumin is activated in liver progenitor cells. Albumin transcription in these cells is regulated by HNF4α or FOXA2. Taken together, HNF4α, C/EBPα and FOXA2 form a hierarchical regulatory network that ensures stable albumin expression even in pathophysiological conditions.
2022-04-06 | GSE181201 | GEO
Project description:Insults to the cerebral cortex, such as trauma, ischemia or infections, may result in the development of epilepsy, one of the most common neurological disorders. Previous studies have suggested that perturbations in neurovascular integrity and breakdown of the blood-brain barrier (BBB) lead to neuronal hypersynchronization and epileptiform activity, but the underlying mechanisms are unknown. As with BBB opening, treatment with albumin or with TGF-β1 results in the development of hypersynchronized epileptiform activity. Given the latent period before the appearance of epileptiform activity, we hypothesized the underlying mechanism is a transcriptional response which would be similar for BBB breakdown and exposure to albumin or TGF-β1. In search of a common pathway and transcriptional activation pattern we performed a genome wide analysis. Genomic expression analyses demonstrated similar expression patterns for BBB opening, albumin and TGF-β1 exposure. Most importantly, TGF-β pathway blockers suppressed most albumin-induced transcriptional changes.
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Project description:Insults to the cerebral cortex, such as trauma, ischemia or infections, may result in the development of epilepsy, one of the most common neurological disorders. Previous studies have suggested that perturbations in neurovascular integrity and breakdown of the blood-brain barrier (BBB) lead to neuronal hypersynchronization and epileptiform activity, but the underlying mechanisms are unknown. As with BBB opening, treatment with albumin or with TGF-?1 results in the development of hypersynchronized epileptiform activity. Given the latent period before the appearance of epileptiform activity, we hypothesized the underlying mechanism is a transcriptional response which would be similar for BBB breakdown and exposure to albumin or TGF-?1. In search of a common pathway and transcriptional activation pattern we performed a genome wide analysis. Genomic expression analyses demonstrated similar expression patterns for BBB opening, albumin and TGF-?1 exposure. Most importantly, TGF-? pathway blockers suppressed most albumin-induced transcriptional changes. RNA was extracted from cortical regions of rats treated with sodium deoxycholate (DOC, to induce BBB opening), albumin or TGF-?1 for various durations (7/8, 24, 48hr). Control RNA was extracted from a sham-operated animal and one array was run for each treatment and time point A second set of animals (labeled as Set 2) was treated with either albumin (n=3) or albumin in the presence of TGF-? receptor blockers (n=4; TGF-?R1 kinase activity inhibitor SB431542 and TGF-?R2 antibody) and sacrificed 24 hr following treatment. Sham-operated animals served as controls (n=2).
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