Dynamic Epigenetic Regulation of miR-10 Family Governs the Caudalization of Floor Plate Neural Progenitors

Abstract

Background: MicroRNAs (miRNAs) are an emerging class of non-coding endogenous RNAs that participated in multiple cellular processes, including cell differentiation, proliferation and signaling/signal transduction. We would like to scrutinize the contribution for miRNAs in the differentiation and caudalization during neural differentiation. Methods: We used well-established protocols to differentiate NTERA-2 (NT2) and human embryonic stem cells (hESCs) into neural progenitor. Bioinformatical analysis were performed to identify pathways regulated by miR-10 family during neural differentiation and caudalization. Results: Directed differentiation of NT2 cells under retinoic acid (RA) treatment resulted in profound changes in the HOX cluster gene patterns as expected, resulting in elevation of miR-10 family members embedded within HOX clusters. Loss of function experiments confirmed that downregulation of miR-10a and -10b impaired RA-induced NT2 differentiation and caudalization, with decreased expression of neural markers. In addition, overexpression of miR-10a alone in hESCs drove the caudalization of human neural progenitor cells towards the hindbrain fate. Of note, nuclear receptor corepressor 2 (NCOR2) was identified as the crucial target responsible for the expression of miR-10 family and their action on neural caudalization. Bioinformatical analysis further found that miR-10 incurred dynamic mitochondrial regulation in hESCs-derived neural progenitors. Conclusions: Our results drilled into the unexplored epigenetic control by miR-10 in regulating RA-induced neural caudalization. It was believed that such alteration in progenitor cell fate was the result of miR-10 which regulated HOX cluster expression and mitochondrial network along neural differentiation.

Keywords

• Neural development
• microRNA
• caudalization
• mitochondrial regulation