Transcriptional profiling of Hutchinson-Gilford Progeria syndrome fibroblasts reveals deficits in mesenchymal stem cell commitment to differentiation related to early events in endochondral ossification

Abstract

AbstractHutchinson-Gilford Progeria Syndrome results from a mutation in Lamin A, and it is characterized by the incorporation of progerin into the nuclear lamina. Progerin expression leads to alterations in genome architecture, nuclear morphology, and epigenetic states, which in turn cause 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. We observe that these fibroblasts carry abnormal transcriptional signatures, centering around five main 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 that a cohort of genes related to endochondral ossification and chondrogenic commitment show altered expression patterns in children aged four to seven years old, where this differentiation program starts in earnest, related to the growth of long bones. We further report changes in lamin associated domains and 3D genome organization around a cohort of genes of interest, identified in this study.