Transcriptional profiling of Hutchinson-Gilford Progeria syndrome fibroblasts reveals deficits in mesenchymal stem cell commitment to differentiation related to early events in endochondral ossification.
Rebeca San MartinPriyojit DasJacob T SandersAshtyn M HillRachel Patton McCordPublished in: eLife (2022)
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.
Keyphrases
- genome wide
- poor prognosis
- gene expression
- dna methylation
- single cell
- mesenchymal stem cells
- extracellular matrix
- bone marrow
- case report
- transcription factor
- end stage renal disease
- stem cells
- copy number
- genome wide identification
- induced apoptosis
- newly diagnosed
- chronic kidney disease
- ejection fraction
- binding protein
- adipose tissue
- traumatic brain injury
- skeletal muscle
- heat shock
- quality improvement
- bone mineral density
- fatty acid
- cell fate
- cell free
- cell cycle arrest
- cell proliferation
- cell therapy
- cell death
- clinical evaluation
- umbilical cord
- heat stress
- wild type