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Naked mole rat cells show resistance to iPSC reprogramming and signs of more stable epigenome

ABSTRACT: Naked mole rat (NMR) is a valuable model for aging and cancer research due to its exceptional longevity and resistance to tumorigenesis. In an effort to generate NMR induced pluripotent stem cells (iPSCs) we observed that reprogramming efficiency of NMR fibroblasts in repsonse to OSKM overexpression was drasticaly lower than that of mouse fibroblasts. To understand the cause of NMR resistance to reprogramming we screened for factors that improve reprogramming effciency. We identified that expression of SV40 Large T (LT) dramatically improved reprogramming of NMR fibroblasts. Inactivation of Rb alone, but not p53, was suffcient to improve reprogramming effciency suggesting that NMR chromatin structure is refractory to reprogramming. Analysis of global histone landscape using quantitative mass spectrometry revealed that NMR fibroblasts had higer levels of repressive H3K27 methylation marks, and lower levels of activating H3K27 acetylation mark than the mouse fibroblasts. Furthermore, the NMR cells had lower levels of permissive H2A.Z acetylation marks. ChIP showed that of E-cadherin had repressive H3K9me3 histone mark in the NMR, but was poised with a bivalent H3K4me3/H3K27me3 in the mouse. Expression of LT reduced the levels of H3K9me3 mark on E-cadherin promoter. ATAC-seq revealed that NMR had more open chromatin globally, however, NMR promoters were more closed than mouse promoters. Expression of LT antigen led to massive opening of the NMR promoters including gene promoters required for reprogramming. Cumulatively, these data suggest that NMR has more stable epigenome than mouse, which resists reprogramming and may contribute to NMR longevity and cancer resistance.

ORGANISM(S): Mus musculus Heterocephalus glaber

PROVIDER: GSE83585 | GEO | 2017/06/21

SECONDARY ACCESSION(S): PRJNA326430

REPOSITORIES: GEO

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Project description:The immune system consists of a network of specialized cells and processes that protect the organism from diseases and regulates tissue repair. Natural killer (NK) cells and the αβ and γδ T cells comprise the cytotoxic arm of the immune system and have evolved to detect and eradicate cells infected with pathogens and affected by malignancies, in order to prevent their spread and subsequent tissue damage. The naked mole-rat (NMR; Heterocephalus glaber) exhibits an unusually long lifespan relative to its body size, remarkable cancer resistance, and a surprising absence of NK cells, likely lost during its evolution. So far, little is known about NMR T cells in terms of the subsets they comprise, the evolution of the genes that regulate their function, the diversity of their clonotypes, and the organ in which they mature – the thymus. Using single-cell RNA sequencing (scRNA-seq), we find that NMRs have a large population of circulating γδT cells, comprising two subsets, one with an activated cytotoxic profile. Using comparative genomics, we find that the NMR genome maintains a large diversity of γ and δ variable T-cell receptor (TCR) regions, relative to that in other mammalian genomes. We devise a novel TCR scRNA-seq approach, which reveals that the NMR cytotoxic γδT-cell subset harbors a dominant clonotype, and that, in contrast to mouse, the clonotypic diversity of NMR CD8 αβT cells is significantly lower than that of its CD4 αβT cells. The latter suggests that NMRs have evolved under a relaxed intracellular pathogenic selective pressure, consistent with the loss of their NK cells. We corroborate this by showing that the genomic diversity of NMR MHC-I genes, relative to that of MHC-II genes, is considerably smaller than in other mammalian genomes. In line with these findings, we further show that NMR thymi in early life are considerably smaller compared to mouse thymi, yet by middle age thymi of both species show equivalent signs of involution. Our study thus sheds significant light on NMR T cells and moves us one step closer towards understanding the contributions of the immune system to the remarkable longevity and cancer resistance of this species.

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Naked mole rat cells show resistance to iPSC reprogramming and signs of more stable epigenome

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