Abstract
Sin3 is a transcriptional corepressor for REST silencing machinery that represses multiple neuronal genes in non-neuronal cells. However, functions of Sin3 (Sin3A and Sin3B) in suppression of neuronal phenotypes are not well characterized. Herein we show that Sin3A knockdown impedes the repressive activity of REST and enhances differentiation of pluripotent P19 cells into electrophysiologically active neurons without inducing astrogenesis. It is also found that silencing Sin3B induces neurogenesis of P19 cells with a lower efficiency than Sin3A knockdown. The results suggest that Sin3A has a more profound effect on REST repressive machinery for silencing neuronal genes in P19 cells than Sin3B. Furthermore, we show that a peptide inhibitor of Sin3A-REST interactions promotes differentiation of P19 cells into functional neurons. Observations made in studies using genetic deletion and a synthetic inhibitor suggests that Sin3A plays an important role in the repression of neuronal genes by the REST regulatory mechanism.
Highlights
Through which various silencing factors or epigenetic modifiers are recruited to REST for its repressive function (Supplementary Fig. S1)
To examine whether suppression of Sin3A or Sin3B activity impedes the repressive function of REST and enhances development of neuronal phenotypes, loss-of-function analyses were conducted in pluripotent P19 cells using Sin3A and Sin3B selective shRNAs
In the study described above, we have shown that Sin3A knockdown impedes REST repressive functions and promotes differentiation of pluripotent P19 cells into neurons
Summary
Through which various silencing factors or epigenetic modifiers are recruited to REST for its repressive function (Supplementary Fig. S1). We have for the first time investigated the effect of suppression of Sin3A and Sin3B activities on neuronal differentiation of pluripotent cells. The results of knockdown studies show that silencing Sin3A abrogates the repressive activity of REST and enhances neuronal differentiation of pluripotent P19 cells to a higher degree than Sin3B knockdown. The findings suggest that Sin3A is a more important corepressor of REST functions that restrict neuronal phenotypes in pluripotent cells than Sin3B. Sin3A knockdown promotes differentiation of P19 cells into electrophysiologically active neurons without generating astrocytes. We show that a peptide inhibitor of binding of Sin3A to REST triggers differentiation of P19 cells into functional neurons but does not promote astrocyte differentiation
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