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| Status |
Public on Jul 10, 2020 |
| Title |
Collapse of the hepatic gene regulatory network in the absence of FoxA factors |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
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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| Overall design |
We depleted all three FoxA genes in 8 week-old mice by injecting adeno-associated virus 8 (AAV8) carrying the gene for Cre recombinase under the control of the hepatocyte-specific thyroid-binding globulin (Tbg) promoter to adult FoxA1L/L/FoxA2 L/L/FoxA3-/- mice and validated FoxA depletion (FoxA triple null). As controls we injected the same transgenes with AAV expressing GFP. FoxA triple nulls were compared also to FoxA1/A2 lox animals, FoxA1/A2 cre alfp and to hepatoblast and new-born RNA-seq data. In addition, RNA-seq was also performed on HNF4a null livers depleted in adult livers.
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| Web link |
http://10.1101/gad.337691.120
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| Contributor(s) |
Reizel Y, Morgan A, Kaestner KH |
| Citation(s) |
32561546 |
| |
| Submission date |
Nov 14, 2019 |
| Last update date |
Jul 10, 2020 |
| Contact name |
Klaus H Kaestner |
| E-mail(s) |
kaestner@pennmedicine.upenn.edu
|
| Organization name |
University of Pennsylvania
|
| Department |
Department of Genetics and Institute for Diabetes Obesity and Metabolism, Perelman School of Medicine
|
| Street address |
University of Pennsylvania, 12-126 Smilow Center for Translational Research, 3400 Civic Center Boulevard
|
| City |
Philadelphia |
| State/province |
PA |
| ZIP/Postal code |
19104-5156 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (51)
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|
| Relations |
| BioProject |
PRJNA589651 |
| SRA |
SRP229988 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE140423_ATAC_combined_TKOl.bw |
5.0 Gb |
(ftp)(http) |
BW |
| GSE140423_ATAC_combined_control.bw |
9.5 Gb |
(ftp)(http) |
BW |
| GSE140423_Comparison_FoxA_triple_null_vs_FoxA12crealfp_summary.txt.gz |
302.8 Kb |
(ftp)(http) |
TXT |
| GSE140423_Comparison_FoxA_triple_null_vs_control_no_deletion.txt.gz |
171.4 Kb |
(ftp)(http) |
TXT |
| GSE140423_Comparison_Hepatobalst_to_adult_hepatocytes_DE_summary.txt.gz |
469.3 Kb |
(ftp)(http) |
TXT |
| GSE140423_Comparison_Newborn_hepatocytes_to_adult_hepatocytesDE_summary.txt.gz |
429.2 Kb |
(ftp)(http) |
TXT |
| GSE140423_Copmparison_Hepatobalst_to_adult_FoxA_triple_null_DE_summary.txt.gz |
474.2 Kb |
(ftp)(http) |
TXT |
| GSE140423_FoxA_triple_null_compared_with_FoxA3_null.txt.gz |
360.2 Kb |
(ftp)(http) |
TXT |
| GSE140423_H3k27ac.Control.mean.bw |
298.3 Mb |
(ftp)(http) |
BW |
| GSE140423_H3k27ac.KO.mean.bw |
284.5 Mb |
(ftp)(http) |
BW |
| GSE140423_H3k4me1.Control.mean.bw |
435.0 Mb |
(ftp)(http) |
BW |
| GSE140423_H3k4me1.KO.mean.bw |
430.7 Mb |
(ftp)(http) |
BW |
| GSE140423_HNF4a_in_control.bw |
779.7 Mb |
(ftp)(http) |
BW |
| GSE140423_HNF4a_in_tko.bw |
636.0 Mb |
(ftp)(http) |
BW |
| GSE140423_HNF4a_peaks_in_control.bed.gz |
532.7 Kb |
(ftp)(http) |
BED |
| GSE140423_HNF4a_vs_control_DE_sumary.txt.gz |
433.8 Kb |
(ftp)(http) |
TXT |
| GSE140423_RPKM_matrix_of_all_samples.txt.gz |
2.5 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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