Behera, Rithika
(2025)
Transcription factor regulation in pulmonary vascular disease and dermal fibrosis in Systemic Sclerosis.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Systemic Sclerosis (SSc) is a rare autoimmune disorder characterized by vasculopathy and fibrosis of the skin and internal organs that lead to multi organ dysfunction. In SSc, changes in micro vessels, initiated by damage and apoptosis of endothelial cells is thought to trigger reduced blood flow and tissue ischemia, leading to vascular manifestations such as Raynaud’s phenomenon, digital ulcers, interstitial lung disease (ILD), and pulmonary hypertension (PH). In the skin, dermal fibroblasts secrete large amounts of extra cellular matrix proteins and can also form myofibroblasts which can drive pathogenic dermal fibrosis.
The interplay between chromatin landscape and transcription factors has an important role in governing the gene regulatory networks and transcriptome of cells, which in turn dictate the cell state as healthy or diseased. The origin of fibrosis and inflammatory pathways in the lungs and skin of SSc patients are not well established and through our study we have found FOSL2 expression in endothelial cells and TGF-β1 in dermal fibroblasts to be a key driver in initiating and maintaining the pathogenesis and inflammation observed in the vasculature and skin of SSc patients respectively.
By analyzing changes in chromatin accessibility and gene expression using single-cell technologies, we show here that FOSL2 is predicted to regulate the altered state of endothelial cells from SSc-ILD patients with PH. Re-examining the endothelial cell states in mice overexpressing Fosl2 using sing-cell RNA sequencing and comparing the gene expression in murine and human patient models indicates that Fosl2 drives downstream gene expression seen in both human and murine PH, and when overexpressed binds to cis elements showing upregulated transcription factor binding in human SSc-ILD-PH lungs. Similarly, using single-cell technologies in the dermal fibroblasts of SSc patients we have identified open chromatin regions in fibrotic genes, which are concordant with transcriptional upregulation in myofibroblasts from SSc skin due to TGF-β1 activity. Through this study, we present the role of transcription factors in influencing cell type specific gene regulation and maintaining disease activity in SSc.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
| Title | Member | Email Address | Pitt Username | ORCID |
|---|
| Thesis Advisor | Lafyatis, Robert | | | | | Committee Chair | Locker, Joseph | | | | | Committee Member | Das, Jishnu | | | | | Committee Member | Poholek, Amanda | | | | | Committee Member | Vodovotz, Yoram | | | |
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| Date: |
23 January 2025 |
| Date Type: |
Publication |
| Defense Date: |
20 June 2024 |
| Approval Date: |
23 January 2025 |
| Submission Date: |
3 December 2024 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
166 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Systemic Sclerosis |
| Date Deposited: |
23 Jan 2025 19:57 |
| Last Modified: |
23 Jan 2025 19:57 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/47160 |
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