The RNA–Methyltransferase Misu (NSun2) Poises Epidermal Stem Cells to Differentiate

Abstract

Homeostasis of most adult tissues is maintained by balancing stem cell self-renewal and differentiation, but whether post-transcriptional mechanisms can regulate this process is unknown. Here, we identify that an RNA methyltransferase (Misu/Nsun2) is required to balance stem cell self-renewal and differentiation in skin. In the epidermis, this methyltransferase is found in a defined sub-population of hair follicle stem cells poised to undergo lineage commitment, and its depletion results in enhanced quiescence and aberrant stem cell differentiation. Our results reveal that post-transcriptional RNA methylation can play a previously unappreciated role in controlling stem cell fate.

NSun2 Deficiency Protects Endothelium From Inflammation via mRNA Methylation of ICAM-1

“…A substantial reduction in NSun2 and loss of NSun2 expression were observed in various tissues of heterozygous rats (NSun2 +/− ) and homozygous rats (NSun2 −/− ), respectively (Online Figure IVD). Consistent with the observations from NSun2-deficient mice, 39,40 …”

“…NSun2 has been implicated in the regulation of cell proliferation, 36,44 stem cell differentiation, 39 testis differentiation, 40 and human cancers. 36, 45 The present study suggests that NSun2 is also a positive determinant for vascular endothelial inflammation and arteriosclerosis (Figures 1-5).…”

“…30,31 The fluctuation of NSun2 in the cell cycle and in stem cell differentiation is also linked to the function of NSun2 in these processes. 39,44 Regulation at the transcriptional level is important for the expression of NSun2 during these processes. 36,39 In addition, posttranslational modification influences the methyltransferase activity of NSun2.…”

Post-transcriptional modifications in development and stem cells

“…Loss of Nsun2 causes significant delays in cell differentiation in skin and testis in mice (Blanco et al, 2011;Hussain et al, 2013c). In adult mouse skin, NSUN2 is most highly expressed in a restricted population of committed progenitor cells in growing hair follicles, and loss of Nsun2 delays stem cell differentiation (Blanco et al, 2011).…”

“…In adult mouse skin, NSUN2 is most highly expressed in a restricted population of committed progenitor cells in growing hair follicles, and loss of Nsun2 delays stem cell differentiation (Blanco et al, 2011). Likewise, NSUN2 is expressed in an undifferentiated and proliferative population of committed progenitor cells in mouse skin tumours, and loss of Nsun2 expands the tumour-initiating cell population at the expense of differentiation, resulting in enhanced tumour growth .…”