Naked Mole Rat Cells Have a Stable Epigenome that Resists iPSC Reprogramming

Abstract

SummaryNaked mole rat (NMR) is a valuable model for aging and cancer research due to its exceptional longevity and cancer resistance. We observed that the reprogramming efficiency of NMR fibroblasts in response to OSKM was drastically lower than that of mouse fibroblasts. Expression of SV40 LargeT antigen (LT) dramatically improved reprogramming of NMR fibroblasts. Inactivation of Rb alone, but not p53, was sufficient to improve reprogramming efficiency, suggesting that NMR chromatin may be refractory to reprogramming. Analysis of the global histone landscape revealed that NMR had higher levels of repressive H3K27 methylation marks and lower levels of activating H3K27 acetylation marks than mouse. ATAC-seq revealed that in NMR, promoters of reprogramming genes were more closed than mouse promoters, while expression of LT led to massive opening of the NMR promoters. These results suggest that NMR displays a more stable epigenome that resists de-differentiation, contributing to the cancer resistance and longevity of this species.

Proteomics of Long‐Lived Mammals

“…Since a strict maintenance of differentiated state may relate to epigenetic stability, Tan et al. hypothesized that the basal level of histone PTMs may be distinct in the NMR compared to the mouse . Consistent with this idea, they found that the NMR fibroblast histones displayed lower levels of H3K27ac and higher levels of H3K27me1, H3K27me3, and H3K27me1K36me1 peptides.…”

“…Three separate groups attempted to test their limits of self‐identity by generating iPSCs from NMR fibroblasts . Although the efficiency of generating NMR iPSCs was weak and varied among the reports, one result was consistent, i.e., the NMR derived iPSCs show a significantly reduced capacity to form teratomas in mice.…”

The roles of DNA, RNA and histone methylation in ageing and cancer

“…Ageing is accompanied by selective loss and reorganization of heterochromatin and upregulation of transcripts from repeat regions, in particular retrotransposable elements 47 , which are associated with DNA double strand breaks 48,49 and can negatively impact on genome stability and disease 50 . In contrast, a stable epigenome is reported to contribute to longevity and cancer resistance 51 . In addition, locus-specific DNA hypermethylation has been associated with ageing blood and tissues 52,53 and appears to be conserved between mice, monkeys and humans 54 .…”

SV40T reprograms Schwann cells into stem-like cells that can re-differentiate into terminal nerve cells.

“…Oct4, Sox2 and c-myc induce cellular reprogramming [1], and were upregulated in the SV40T SCs. Previous studies have shown that SV40 T can improve reprogramming efficiency [7,19]. The reprogramming of Schwann cells by SV40T may involve cell cycle regulation and Slug activation.…”