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| Status |
Public on May 05, 2023 |
| Title |
Hexokinase 2-mediated gene expression via histone lactylation is required for hepatic stellate cell activation and liver fibrosis (CUT&Tag) |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Lactate was implicated in activation of hepatic stellate cells (HSCs). However, the mechanism by which lactate exerts its effect remains elusive. We show that hexokinase 2 (HK2) is sufficient to change gene expression by histone lactylation but not histone acetylation. Using RNA-seq and CUT&Tag chromatin profiling, we found that induction of HK2 expression in activated HSCs is required for the induced gene expression by elevating histone lactylation. Inhibiting histone lactylation by Hk2 deletion or pharmacological inhibition of lactate production diminishes HSC activation, whereas exogenous lactate but not acetate supplementation rescues the activation phenotype. Thus, lactate produced by activated HSCs determines the HSC fate via histone lactylation. We found that histone acetylation competes with histone lactylation, which could explain why class I HDAC inhibitors impede HSC activation. Finally, HSC-specific or systemic deletion of HK2 inhibits HSC activation and liver fibrosis in vivo. Therefore, we provide evidence that HK2 may be an effective therapeutic target for liver fibrosis.
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| Overall design |
Genomic occupancy profiling of H3K18la and H3K18ac for quiescent (QS), activated (ACT), activated HK2-deleted (KO), KO with lactate-treated (LAC) mouse primary HSCs.
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| Contributor(s) |
Hay N, Rho H |
| Citation(s) |
37463576 |
| |
| Submission date |
Apr 06, 2023 |
| Last update date |
Aug 04, 2023 |
| Contact name |
Nissim Hay |
| E-mail(s) |
nhay@uic.edu
|
| Organization name |
University of Illinois Chicago
|
| Department |
BMG
|
| Street address |
900 South Ashland Ave
|
| City |
Chicago |
| State/province |
IL |
| ZIP/Postal code |
60607 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (20)
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| This SubSeries is part of SuperSeries: |
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| Relations |
| BioProject |
PRJNA953056 |
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