Transcriptional profiling of Hutchinson-Gilford Progeria syndrome fibroblasts reveals deficits in mesenchymal stem cell commitment to differentiation related to early events in endochondral ossification
- University of Tennessee at Knoxville, United States
Abstract
The expression of a mutant Lamin A, progerin, in Hutchinson-Gilford Progeria Syndrome leads to alterations in genome architecture, nuclear morphology, epigenetic states, and altered phenotypes in all cells of the mesenchymal lineage. Here, we report a comprehensive analysis of the transcriptional status of patient derived HGPS fibroblasts, including nine cell lines not previously reported, in comparison with age-matched controls, adults, and old adults. We find that Progeria fibroblasts carry abnormal transcriptional signatures, centering around several functional hubs: DNA maintenance and epigenetics, bone development and homeostasis, blood vessel maturation and development, fat deposition and lipid management, and processes related to muscle growth. Stratification of patients by age revealed misregulated expression of genes related to endochondral ossification and chondrogenic commitment in children aged four to seven years old, where this differentiation program starts in earnest. Hi-C measurements on patient fibroblasts show weakening of genome compartmentalization strength but increases in TAD strength. While the majority of gene misregulation occurs in regions which do not change spatial chromosome organization, some expression changes in key mesenchymal lineage genes coincide with lamin associated domain misregulation and shifts in genome compartmentalization.
Data availability
All RNA-seq and Hi-C data contributed by this study is available on GEO at GSE206707 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE206707).
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Epigenetic deregulation of lamina-associated domains in Hutchinson-Gilford Progeria Syndrome (RNA-Seq)NCBI Gene Expression Omnibus, GSE150137.
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Predicting age from the transcriptome of human dermal fibroblastsNCBI Gene Expression Omnibus, GSE113957.
Article and author information
Author details
Rachel Patton McCord
Funding
National Institute of General Medical Sciences (R35GM133557)
- Rachel Patton McCord
American Cancer Society (134060-PF-19-183-01-CSM)
- Rebeca San Martin
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Cheryl Ackert-Bicknell, University of Colorado, United States
Version history
- Preprint posted: June 21, 2022 (view preprint)
- Received: June 22, 2022
- Accepted: December 29, 2022
- Accepted Manuscript published: December 29, 2022 (version 1)
- Version of Record published: January 11, 2023 (version 2)
Copyright
© 2022, San Martin et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Transcriptional profiling of Hutchinson-Gilford Progeria syndrome fibroblasts reveals deficits in mesenchymal stem cell commitment to differentiation related to early events in endochondral ossification
eLife 11:e81290.
https://doi.org/10.7554/eLife.81290
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