Transcriptional profiling of Hutchinson-Gilford Progeria syndrome fibroblasts reveals deficits in mesenchymal stem cell commitment to differentiation related to early events in endochondral ossification
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eLife assessment
This manuscript is of interest to researchers investigating genetic mechanisms of aging and transcriptional regulation of developmental processes in mesenchyme-derived tissues. In this study, fibroblast cell lines from patients with and without Hutchinson-Gilford Progeria were compared to pinpoint the molecular mechanisms leading to the phenotypes of persons with this condition. The identification of five major dysregulated functional hubs in fibroblast cell lines derived from Hutchinson-Gilford Progeria Syndrome (HGPS) patients provides a unique opportunity for others working on this disorder to utilize animal models to validate the authors' hypotheses.
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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 4–7 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.
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eLife assessment
This manuscript is of interest to researchers investigating genetic mechanisms of aging and transcriptional regulation of developmental processes in mesenchyme-derived tissues. In this study, fibroblast cell lines from patients with and without Hutchinson-Gilford Progeria were compared to pinpoint the molecular mechanisms leading to the phenotypes of persons with this condition. The identification of five major dysregulated functional hubs in fibroblast cell lines derived from Hutchinson-Gilford Progeria Syndrome (HGPS) patients provides a unique opportunity for others working on this disorder to utilize animal models to validate the authors' hypotheses.
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Reviewer #1 (Public Review):
Overall this is an interesting and comprehensive examination of gene expression in Hutchinson-Gilford Progeria using a mix of pre-collected and de novo fibroblast cell lines. Comparisons in expression are made between age groups of Hutchinson-Gilford Progeria patients and with chronological age-matched and "aging" matched normal controls. This work is then extended to explore the impact of the accumulation of progerin on chromosome compartment use and lamina-associated domain distribution. The focus of the remainder of the paper is on the impact of the Hutchinson-Gilford Progeria mutation on signatures reflective of the three cell types that arise from mesenchymal progenitors, namely osteoblasts, chondrocytes, and adipocytes.
Strengths:
This work expands greatly on previous work in this area. Batch smoothing …
Reviewer #1 (Public Review):
Overall this is an interesting and comprehensive examination of gene expression in Hutchinson-Gilford Progeria using a mix of pre-collected and de novo fibroblast cell lines. Comparisons in expression are made between age groups of Hutchinson-Gilford Progeria patients and with chronological age-matched and "aging" matched normal controls. This work is then extended to explore the impact of the accumulation of progerin on chromosome compartment use and lamina-associated domain distribution. The focus of the remainder of the paper is on the impact of the Hutchinson-Gilford Progeria mutation on signatures reflective of the three cell types that arise from mesenchymal progenitors, namely osteoblasts, chondrocytes, and adipocytes.
Strengths:
This work expands greatly on previous work in this area. Batch smoothing and increased number of cell lines allowed for more power for discovery and for better resolution of the analysis. This powerful data set represents a treasure mine of information that will be of high use to the field.
Weaknesses:
This work is entirely based on fibroblasts. While this weakness is acknowledged by the authors, the validity of the conclusions is not validated in any way to demonstrate that the fibroblast is sufficient in this instance. Rather the authors rely on a series of references from other biological systems. Comparisons are made between a parent and affected offspring, but this is restricted to one pair of samples.
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Reviewer #2 (Public Review):
San Martin et al utilize an extensive set of genomic and bioinformatics tools to perform a comprehensive analysis of the transcriptional status of HGPS fibroblast cell lines, which suggests dysregulation of pathways critical for the development and maintenance of mesenchymal tissues affected in this disorder. The authors conclude, based on transcriptional profiling of these cells, that mesenchymal stem cell depletion exacerbated by defective tissue repair responses results in the HGPS bone phenotype. An important strength of this manuscript is the comparison of HGPS cells not only to age-matched controls but to healthy old adults as well, leading this reviewer to question the validity of describing HGPS as a premature aging disorder. A major shortcoming of this work is the drawing of conclusions on …
Reviewer #2 (Public Review):
San Martin et al utilize an extensive set of genomic and bioinformatics tools to perform a comprehensive analysis of the transcriptional status of HGPS fibroblast cell lines, which suggests dysregulation of pathways critical for the development and maintenance of mesenchymal tissues affected in this disorder. The authors conclude, based on transcriptional profiling of these cells, that mesenchymal stem cell depletion exacerbated by defective tissue repair responses results in the HGPS bone phenotype. An important strength of this manuscript is the comparison of HGPS cells not only to age-matched controls but to healthy old adults as well, leading this reviewer to question the validity of describing HGPS as a premature aging disorder. A major shortcoming of this work is the drawing of conclusions on pathomechanisms of HGPS in multiple mesenchyme-derived tissues based on fibroblast transcriptional and epigenetic profiles which are, however, acknowledged by the authors.
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