Abstract
In vitro, mouse embryonic stem (ES) cells can differentiate into many somatic cell types, including neurons and glial cells. When cultured in serum-free medium, ES cells convert spontaneously and efficiently to a neural fate. Previous studies have shown that the neural conversion of mouse ES cells includes both the participation of neural-specific transcription factors and the regulation of epigenetic modifications. However, the intracellular mechanism underlying this intrinsic transition still remains to be further elucidated. Herein, we describe a long intergenic non-coding RNA, LincRNA1230, which participates in the regulation of the neural lineage specification of mouse ES cells. The ectopic forced expression of LincRNA1230 dramatically inhibited mouse ES cells from adopting a neural cell fate, while LincRNA1230 knockdown promoted the conversion of mouse ES cells towards neural progenitors. Mechanistic studies have shown that LincRNA1230 inhibits the activation of early neural genes, such as Pax6 and Sox1, through the modulation of bivalent modifications (tri-methylation of histone3 lysine4 and histone3 lysine27) at the promoters of these genes. The interaction of LincRNA1230 with Wdr5 blocked the localization of Wdr5 at the promoters of early neural genes, thereby inhibiting the enrichment of H3K4me3 modifications at these loci. Collectively, these findings revealed a crucial role for LincRNA1230 in the regulation of the neural differentiation of mouse ES cells.
Highlights
Mouse embryonic stem (ES) cells are initially derived from pre-implanted blastocysts (Evans and Kaufman, 1981) and have the ability to develop into all three germ lines (Ying et al, 2003)
We subsequently examined the expression of several long intergenic non-coding RNA (lincRNA) that are predicted to be associated with neural ectoderm differentiation in previous studies (Guttman et al, 2011) during neural differentiation
As LincRNA1230 is down regulated during SFEB culture, we examined whether the decreased expression of LincRNA1230 is required for neural lineage commitment
Summary
Mouse ES cells are initially derived from pre-implanted blastocysts (Evans and Kaufman, 1981) and have the ability to develop into all three germ lines (Ying et al, 2003). ES cells can differentiate into various somatic cell types with specific biological functions, such as myocardial cells (Siu et al, 2007), pancreatic β cells (Pagliuca et al, 2014), neurons (Kamiya et al, 2011; Selvaraj et al, 2012; Watanabe et al, 2005) and glial cells (Selvaraj et al, 2012). The establishment of the in vitro neural differentiation system has provided insight into the mechanisms underlying the nervous system development of vertebrates. Using this serum-free neural differentiation model, scientists have revealed the regulatory function of many transcription factors (TFs), such as Zfp521 and Oct, which play important roles in the conversion of mouse ES cells into neural progenitors. Zfp521 interacts with the co-activator P300 to initiate the expression of several early neural genes, such as Sox, Sox, and Pax (Kamiya et al., Wang, C., et al Sci China Life Sci May (2016) Vol. No.5
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