Research Article: An inhibitory role of progerin in the gene induction network of adipocyte differentiation from iPS cells

Date Published: April 14, 2013

Publisher: Impact Journals LLC

Author(s): Zheng-Mei Xiong, Christina LaDana, Di Wu, Kan Cao.



Lipodystrophies, characterized by partial or complete loss of adipose tissue, have been associated with mutations in the lamin A gene. It remains unclear how lamin A mutants interfere with adipose tissue formation. Hutchinson–Gilford progeria syndrome (HGPS) presents the most severe form of lamin A-associated diseases, whose patients show a complete loss of subcutaneous fat. Using iPSCs reprogrammed from HGPS fibroblasts, we induced adipocyte formation from iPSC derived embryoid bodies or from iPSC derived mesenchymal stem cells. Both approaches revealed a severe lipid storage defect in HGPS cells at late differentiation stage, faithfully recapitulating HGPS patient phenotype. Expression analysis further indicated that progerin inhibited the transcription activation of PPARγ2 and C/EBPα, but had little effects on the early adipogenic regulators. Our experiments demonstrate two comparable approaches of in vitro modeling lipodystrophies with patient-specific iPSCs, and support a regulatory role of lamin A in the terminal differentiation stage of adipogenesis.

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Adipocytes are essential regulators of whole-body energy homeostasis. Compared to other cell types with esterified lipids, these cells are unique in the large quantity of lipids that they can store. In addition, adipocytes secrete proteins that regulate diverse processes including blood pressure control, immune response, angiogenesis and reproductive function [1-3]. Partial or complete loss of adipose tissue characterizes a growing group of genetic disorders known as lipodystrophies [1, 4, 5].

Recently, several groups showed the absence of lamin A/C expression in iPSCs [15, 16, 29]. In accordance with their reports, we found the silencing of the LMNA gene transcription in iPSCs, which was coupled with a reduction in H3K4me3 on the promoter of LMNA (Figure 1). Methylation study indicated LMNA gene silencing in iPSCs was not controlled by DNA methylation [15]. Interestingly, a recent study showed a brain specific microRNA (MiR-9) to be responsible for the down-regulation of lamin A but not lamin C in neurons [17]. Future work is required to decipher the regulation of lamin A expression in ESCs /iPSCs. In this study, we showed that lamin B was up-regulated in iPSCs in the absence of lamin A/C, implying a certain total amount of lamin proteins may be needed in iPSCs. It is intriguing since mouse knockout analysis suggests that lamins are not needed for self-renewal and pluripotency in mouse ESCs [14]. The questions of how and why lamin B is up-regulated in iPSCs remain to be explored.





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