Aire Promotes the Self-Renewal of Embryonic Stem Cells Through Lin28

Abstract

Autoimmune regulator (Aire) is one of the most well-characterized molecules in autoimmunity, but its function outside the immune system is largely unknown. The recent discovery of Aire expression in stem cells and early embryonic cells and its function in the self-renewal of embryonic stem (ES) cells highlight the importance of Aire in these cells. In this study, we present evidence that Aire promotes the expression of the pluripotent factor Lin28 and the self-renewal of ES cells. We presented the first evidence that the let-7 microRNA family contributed to the self-renewal promoting effect of Aire on ES cells. Moreover, we showed that Aire and Lin28 are co-expressed in the genital ridge, oocytes, and cleavage-stage embryos, and the expression level of Lin28 is correlated with the expression level of Aire. Although it is widely considered to be a promiscuous gene expression activator, these results indicated that Aire promotes the self-renewal of ES cells through a specific pathway (i.e., the activation of Lin28 and the inhibition of the let-7 microRNA family). The correlation between Aire and Lin28 expression in germ cells and early embryos indicated an in vivo function for Aire in toti-and pluripotent stem cells. This study presents the first molecular pathway that incorporates Aire into the pluripotency network. Moreover, it presents the first evidence that microRNAs contribute to the regulatory function of Aire and highlights a novel function of Aire in stem cell biology and reproduction. These functions reveal novel perspectives for studying the molecular mechanisms behind the establishment and sustenance of pluripotent identity.

Single-cell analyses of X Chromosome inactivation dynamics and pluripotency during differentiation

“…Here, we identified 130 genes enriched in ES cells, including TFs Aire, Rarg, Wt1, Prdm5, and Tcfl5. Aire is a well-known immune response gene that also promotes self-renewal through regulation of microRNA (Gu et al 2010;Bin et al 2012). Rarg is a retinoic acid receptor that is involved in reprogramming of somatic cells to induced pluripotent stem cells through retinoid acid signaling (Wang et al 2011).…”

Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia

“…13). The recognition by AIRE of chromatin state(s) rather than particular DNA sequences would explain how it positively and likely stochastically regulates the expression of so many genes in a singlecell type, and may help to understand Aire's emerging immune system-independent roles in embryonic stem cells and in the testis (Schaller et al 2008;Brahmaraju et al 2011;Bin et al 2012).…”

LIN28: roles and regulation in development and beyond

“…Further investigation by Peng and colleagues identified a number of mRNAs regulated by LIN28 that are important for both growth and translation, supporting its role in the regulation of proliferation . When LIN28 is expressed, it regulates selfrenewal in mouse ESCs as a function of AIRE, the autoimmune regulator (Bin et al, 2012). As in ESCs, proliferation in neural precursor cells is promoted by SOX2 through LIN28 (Cimadamore et al, 2013).…”