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| Status |
Public on Sep 10, 2019 |
| Title |
Chromatin architecture as a checkpoint for NASH-associated liver injury |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Nonalcoholic steatohepatitis (NASH) is a progressive liver disease that is characterized by liver injury, inflammation and fibrosis. NASH pathogenesis is linked to reprogramming of chromatin landscape in the liver that predisposes hepatocytes to stress-induced tissue injury. However, the molecular nature of the putative checkpoint that maintains chromatin architecture and preserves hepatocyte health remains elusive. Here we show that heterogeneous nuclear ribonucleoprotein U (hnRNPU), a nuclear matrix protein that governs chromatin architecture and gene transcription, is a critical factor that couples chromatin disruption to NASH pathogenesis. RNA-seq and ChIP-seq studies revealed an extensive overlap between hnRNPU occupancy and altered gene expression during NASH. Hepatocyte-specific inactivation of hnRNPU disrupted liver chromatin accessibility, activated the molecular signature of NASH and sensitized mice to diet-induced NASH pathogenesis. Mechanistically, hnRNPU deficiency stimulated the expression of a truncated isoform of TrkB that promotes inflammatory signaling in hepatocytes and stress-induced cell death. These findings illustrate a novel mechanism through which disruptions of chromatin architecture drive the emergence of disease-specific signaling patterns that promote liver injury and exacerbate NASH pathogenesis.
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| Overall design |
6 biological replicates were analyzied in each group for ATAC-seq (control vs liver specific knockout); 2 control and 3 liver specific knockout samples were used in RNA-seq
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| Contributor(s) |
Liu T, Xiong J, Lin J |
| Citation(s) |
31469911 |
| Submission date |
May 16, 2019 |
| Last update date |
Sep 10, 2019 |
| Contact name |
Jiandie Lin |
| E-mail(s) |
jdlin@umich.edu
|
| Phone |
7346153512
|
| Organization name |
University of Michigan
|
| Department |
Cell & Developmental Biology, Life Science Institute
|
| Lab |
Jiandie Lin Lab
|
| Street address |
210 Washtenaw Ave
|
| City |
Ann Arbor |
| State/province |
MI |
| ZIP/Postal code |
48103 |
| Country |
USA |
| |
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| Platforms (2) |
| GPL23479 |
BGISEQ-500 (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (17)
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| Relations |
| BioProject |
PRJNA543292 |
| SRA |
SRP198634 |
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