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| Status |
Public on May 16, 2024 |
| Title |
ATP-citrate lyase regulates chromatin-dependent activation and maintenance of the myofibroblast gene program and cardiac fibrosis |
| Organism |
Mus musculus |
| Experiment type |
Other
|
| Summary |
Differentiation of cardiac fibroblasts (CFs) to myofibroblasts is necessary for matrix remodeling and fibrosis in heart failure. We previously reported mitochondrial calcium signaling drives α-ketoglutarate-dependent histone demethylation, promoting the myofibroblast gene program. Here, we investigated the role of ATP-citrate lyase (ACLY), a key enzyme for acetyl-CoA biosynthesis, in histone acetylation regulating myofibroblast formation and persistence in cardiac fibrosis. Inactivation of ACLY prevented, and importantly reversed, myofibroblasts towards quiescence. Genetic deletion of Acly in activated myofibroblasts prevented fibrosis and preserved cardiac function in murine pressure-overload. TGFβ stimulation enhanced ACLY nuclear localization and increased H3K27ac at fibrotic gene loci. Pharmacological inhibition of ACLY or forced nuclear expression of dominant-negative ACLY mutant prevented myofibroblast formation and H3K27ac. Our data indicate nuclear ACLY activity is necessary for myofibroblast differentiation and persistence by maintaining histone acetylation at TGFβ-induced myofibroblast genes. These findings provide novel clinical rational to prevent and reverse pathological fibrosis.
CUT&RUN Sequencing for H3K27ac on the role of ACLY in myofibroblast differentiaton.
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| Overall design |
H3K27ac-enriched DNA using CUT&RUN from cardiac fiborblasts stimulated with or without TGFβ and treated with and without ACLY inhibitor.
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| Contributor(s) |
Lazaropoulos MP, Gibb AA, Chapski DJ, Vondriska TM, Elrod JW |
| Citation missing |
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| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| F30 HL152564 |
The Role of Acetyl-CoA Metabolism in Epigenetic Regulation of Myofibroblast Differentiation |
TEMPLE UNIVERSITY |
Michael Lazaropoulos |
|
| Submission date |
May 08, 2023 |
| Last update date |
May 17, 2024 |
| Contact name |
Michael Panagiotis Lazaropoulos |
| E-mail(s) |
michael.laz@temple.edu, lazaropoulosm@gmail.com
|
| Phone |
+16099691328
|
| Organization name |
Temple University
|
| Department |
Department of Cardiovascular Sciences
|
| Lab |
Elrod Lab
|
| Street address |
3500 North Broad Street
|
| City |
Philadelphia |
| State/province |
PA |
| ZIP/Postal code |
19140 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (15)
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| Relations |
| BioProject |
PRJNA970472 |
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