Changes in nascent chromatin structure regulate activation of the pro-fibrotic transcriptome and myofibroblast emergence in organ fibrosis
Summary: Cell reprogramming to a myofibroblast responsible for the pathological accumulation of extracellular matrix is fundamental to the onset of fibrosis. Here, we explored how condensed chromatin structure marked by H3K72me3 becomes modified to allow for activation of repressed genes to drive em...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-05-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223006478 |
| _version_ | 1797844283468808192 |
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| author | Morgan D. Basta Svetlana Petruk Ross Summer Joel Rosenbloom Peter J. Wermuth Edward Macarak Alex V. Levin Alexander Mazo Janice L. Walker |
| author_facet | Morgan D. Basta Svetlana Petruk Ross Summer Joel Rosenbloom Peter J. Wermuth Edward Macarak Alex V. Levin Alexander Mazo Janice L. Walker |
| author_sort | Morgan D. Basta |
| collection | DOAJ |
| description | Summary: Cell reprogramming to a myofibroblast responsible for the pathological accumulation of extracellular matrix is fundamental to the onset of fibrosis. Here, we explored how condensed chromatin structure marked by H3K72me3 becomes modified to allow for activation of repressed genes to drive emergence of myofibroblasts. In the early stages of myofibroblast precursor cell differentiation, we discovered that H3K27me3 demethylase enzymes UTX/KDM6B creates a delay in the accumulation of H3K27me3 on nascent DNA revealing a period of decondensed chromatin structure. This period of decondensed nascent chromatin structure allows for binding of pro-fibrotic transcription factor, Myocardin-related transcription factor A (MRTF-A) to nascent DNA. Inhibition of UTX/KDM6B enzymatic activity condenses chromatin structure, prevents MRTF-A binding, blocks activation of the pro-fibrotic transcriptome, and results in an inhibition of fibrosis in lens and lung fibrosis models. Our work reveals UTX/KDM6B as central coordinators of fibrosis, highlighting the potential to target its demethylase activity to prevent organ fibrosis. |
| first_indexed | 2024-04-09T17:20:52Z |
| format | Article |
| id | doaj.art-ba372bd90ff342b6bee429d1eaefaafa |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-09T17:20:52Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-ba372bd90ff342b6bee429d1eaefaafa2023-04-19T04:23:12ZengElsevieriScience2589-00422023-05-01265106570Changes in nascent chromatin structure regulate activation of the pro-fibrotic transcriptome and myofibroblast emergence in organ fibrosisMorgan D. Basta0Svetlana Petruk1Ross Summer2Joel Rosenbloom3Peter J. Wermuth4Edward Macarak5Alex V. Levin6Alexander Mazo7Janice L. Walker8Department of Pathology and Genomic Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USACenter for Translational Medicine, The Jane and Leonard Korman Respiratory Institute at the Sidney Kimmel Medial College, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Dermatology and Cutaneous Biology, The Joan and Joel Rosenbloom Research Center for Fibrotic Diseases, Sidney Kimmel Medical College Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Dermatology and Cutaneous Biology, The Joan and Joel Rosenbloom Research Center for Fibrotic Diseases, Sidney Kimmel Medical College Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Dermatology and Cutaneous Biology, The Joan and Joel Rosenbloom Research Center for Fibrotic Diseases, Sidney Kimmel Medical College Thomas Jefferson University, Philadelphia, PA 19107, USAWills Eye Hospital, Philadelphia, PA 19107, USADepartment of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; Corresponding authorDepartment of Pathology and Genomic Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA; Department of Ophthalmology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA; Corresponding authorSummary: Cell reprogramming to a myofibroblast responsible for the pathological accumulation of extracellular matrix is fundamental to the onset of fibrosis. Here, we explored how condensed chromatin structure marked by H3K72me3 becomes modified to allow for activation of repressed genes to drive emergence of myofibroblasts. In the early stages of myofibroblast precursor cell differentiation, we discovered that H3K27me3 demethylase enzymes UTX/KDM6B creates a delay in the accumulation of H3K27me3 on nascent DNA revealing a period of decondensed chromatin structure. This period of decondensed nascent chromatin structure allows for binding of pro-fibrotic transcription factor, Myocardin-related transcription factor A (MRTF-A) to nascent DNA. Inhibition of UTX/KDM6B enzymatic activity condenses chromatin structure, prevents MRTF-A binding, blocks activation of the pro-fibrotic transcriptome, and results in an inhibition of fibrosis in lens and lung fibrosis models. Our work reveals UTX/KDM6B as central coordinators of fibrosis, highlighting the potential to target its demethylase activity to prevent organ fibrosis.http://www.sciencedirect.com/science/article/pii/S2589004223006478EpigeneticsMolecular mechanism of gene regulationMolecular physiologyTranscriptomics |
| spellingShingle | Morgan D. Basta Svetlana Petruk Ross Summer Joel Rosenbloom Peter J. Wermuth Edward Macarak Alex V. Levin Alexander Mazo Janice L. Walker Changes in nascent chromatin structure regulate activation of the pro-fibrotic transcriptome and myofibroblast emergence in organ fibrosis iScience Epigenetics Molecular mechanism of gene regulation Molecular physiology Transcriptomics |
| title | Changes in nascent chromatin structure regulate activation of the pro-fibrotic transcriptome and myofibroblast emergence in organ fibrosis |
| title_full | Changes in nascent chromatin structure regulate activation of the pro-fibrotic transcriptome and myofibroblast emergence in organ fibrosis |
| title_fullStr | Changes in nascent chromatin structure regulate activation of the pro-fibrotic transcriptome and myofibroblast emergence in organ fibrosis |
| title_full_unstemmed | Changes in nascent chromatin structure regulate activation of the pro-fibrotic transcriptome and myofibroblast emergence in organ fibrosis |
| title_short | Changes in nascent chromatin structure regulate activation of the pro-fibrotic transcriptome and myofibroblast emergence in organ fibrosis |
| title_sort | changes in nascent chromatin structure regulate activation of the pro fibrotic transcriptome and myofibroblast emergence in organ fibrosis |
| topic | Epigenetics Molecular mechanism of gene regulation Molecular physiology Transcriptomics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223006478 |
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