Collapse of the hepatic gene regulatory network in the absence of FoxA factors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA589651 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10447148.fastq.gz | Fastqsanger.gz | |||
| SRR10447149.fastq.gz | Fastqsanger.gz | |||
| SRR10447150.fastq.gz | Fastqsanger.gz | |||
| SRR10447151.fastq.gz | Fastqsanger.gz | |||
| SRR10447152.fastq.gz | Fastqsanger.gz |
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Project description:FoxA transcription factors are critical for liver development through their pioneering activity, which initiates a highly complex network thought to become resistant to the loss of any individual hepatic transcription factor via mutual redundancy. To investigate the dispensability of FoxA factors for this regulatory network, we ablated all FoxA genes in the adult liver. Remarkably, loss of FoxA caused a rapid and massive reduction in the expression of key liver genes back to the low levels of the fetal prehepatic endoderm stage, leading to necrosis and lethality within days. Mechanistically, we found FoxA proteins to be required for maintaining chromatin activity, nucleosome positioning and binding by other hepatic transcription factors. Thus, the hepatic gene regulatory network is dependent on the FoxA proteins throughout life.
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Project description:The FoxA transcription factors are critical for liver development through their pioneering activity, which initiates a highly complex regulatory network thought to become progressively resistant to the loss of any individual hepatic transcription factor via mutual redundancy. To investigate the dispensability of FoxA factors for maintaining this regulatory network, we ablated all FoxA genes in the adult mouse liver. Remarkably, loss of FoxA caused rapid and massive reduction in the expression of critical liver genes. Activity of these genes was reduced back to the low levels of the fetal prehepatic endoderm stage, leading to necrosis and lethality within days. Mechanistically, we found FoxA proteins to be required for maintaining enhancer activity, chromatin accessibility, nucleosome positioning, and binding of HNF4α. Thus, the FoxA factors act continuously, guarding hepatic enhancer activity throughout adult life.
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Project description:FOXA pioneer transcription factors (TFs) associate with primed enhancers in endodermal organ precursors. Using a human stem cell model of pancreas differentiation, we here discover that only a subset of pancreatic enhancers is FOXA-primed, whereas the majority is unprimed and engages FOXA upon lineage induction. Primed enhancers are enriched for signal-dependent TF motifs and harbor abundant and strong FOXA motifs. Unprimed enhancers harbor fewer, more degenerate FOXA motifs, and FOXA recruitment to unprimed but not primed enhancers requires pancreatic TFs. Strengthening FOXA motifs at an unprimed enhancer near NKX6.1 renders FOXA recruitment pancreatic TF-independent, induces priming, and broadens the NKX6.1 expression domain. We make analogous observations about FOXA binding during hepatic and lung development. Our findings suggest a dual role for FOXA in endodermal organ development: First, FOXA facilitate signal-dependent lineage initiation via enhancer priming, and second, FOXA enforce organ cell type-specific gene expression via indirect recruitment by lineage-specific TFs.
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Project description:In the HBV transgenic mouse model of chronic infection, the forkhead box protein A/hepatocyte nuclear factor 3 (Foxa/HNF3) family of pioneer transcription factors are required to support postnatal viral demethylation and subsequent HBV transcription and replication. Liver-specific Foxa-deficient mice with hepatic expression of only Foxa3 do not support HBV replication but display biliary epithelial hyperplasia with bridging fibrosis. However, liver-specific Foxa-deficient mice with hepatic expression of only Foxa1 or Foxa2 also successfully restrict viral transcription and replication but display only minimal alterations in liver physiology. These observations suggest that the level of Foxa activity, rather than the combination of specific Foxa genes, is a key determinant of HBV biosynthesis. Together, these findings suggest that targeting Foxa activity could lead to HBV DNA methylation and transcriptional inactivation, resulting in the resolution of chronic HBV infections which are responsible for approximately one million deaths annually worldwide.
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Project description:Iron is a key nutrient for almost all living organisms and paradoxically poorly soluble and consequently poorly bioavailable. To get access to this metal, bacteria have developed many different strategies. One of the most common consists of the use of siderophores, small compounds chelating ferric iron with a very high affinity. Many bacteria are able to produce their own siderophores or use those produced by other microorganisms (exosiderophores) in a piracy strategy. Pseudomonas aeruginosa produces two siderophores, pyoverdine and pyochelin and is able to use a large panel of exosiderophores. We investigated the ability of P. aeruginosa to use nocardamine (NOCA) and ferrioxamine B (DFOB) as exosiderophores under iron-limited planktonic growth conditions. Proteomic and RT-qPCR approaches showed an induction of the transcription and expression of the outer membrane transporter FoxA in the presence of NOCA or DFO in the bacterial environment. Expression of the proteins of the heme or pyoverdine and pyochelin dependent iron uptake pathways were not affected in the presence of these two tris-hydroxamate siderophores. 55Fe uptake assays using foxA mutants demonstrated that ferri-NOCA was exclusively transported by FoxA, while ferri-DFO was transported by FoxA and at least one another unidentified transporter. The crystal structure of FoxA in complex with NOCA revealed very similar siderophore binding sites between NOCA and DFO. Iron uptake by hydroxamate exosiderophores in P. aeruginosa cells is discussed in the light of these results.
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