Long noncoding RNA Sox2ot and transcription factor YY1 co-regulate the differentiation of cortical neural progenitors by repressing Sox2

Jennifer L Knauss,Mary E Donohoe,Tao Wu,Hugo Borges Pinto,Yanzhen Nie,Seung-Nam Kim,Yuelin Shi,Tao Sun,Nan Miao

doi:10.1038/s41419-018-0840-2

Abstract

Long noncoding RNAs (lncRNAs) are emerging as key regulators of crucial cellular processes. However, the molecular mechanisms of many lncRNA functions remain uncharacterized. Sox2ot is an evolutionarily conserved lncRNA that transcriptionally overlaps the pluripotency gene Sox2, which maintains the stemness of embryonic stem cells and tissue-specific stem cells. Here, we show that Sox2ot is expressed in the developing mouse cerebral cortex, where it represses neural progenitor (NP) proliferation and promotes neuronal differentiation. Sox2ot negatively regulates self-renewal of neural stem cells, and is predominately expressed in the nucleus and inhibits Sox2 levels. Sox2ot forms a physical interaction with a multifunctional transcriptional regulator YY1, which binds several CpG islands in the Sox2 locus in a Sox2ot-dependent manner. Similar to Sox2ot, YY1 represses NP expansion in vivo. These results demonstrate a regulatory role of Sox2ot in promoting cortical neurogenesis, possibly by repressing Sox2 expression in NPs, through interacting with YY1.

Highlights

Production of distinct types of neural progenitors and neurons is regulated by coding and noncoding RNAs in the mammalian cerebral cortex[1,2,3,4,5]
We found that YY1 binds to CpG islands at the Sox[2] locus and represses neural progenitor (NP) proliferation, and that this binding is dependent on Sox2 overlapping transcript (Sox2ot)
Both Sox[2] and Sox2ot were expressed in the ventricular zone (VZ) and subventricular zone (SVZ) of cortices at embryonic day 13.5 (E13.5) and E15.5, which correspond to the active stages of neural progenitor expansion (Fig. 1b–e)

Summary

Introduction

Production of distinct types of neural progenitors and neurons is regulated by coding and noncoding RNAs in the mammalian cerebral cortex[1,2,3,4,5]. Though thousands of lncRNAs have been reported, relatively few have been mechanistically characterized Those that have been characterized appear to work through a wide variety of mechanisms, including control of chromatin structure, Sox[2] is a pluripotency gene that maintains the stemness of human and rodent ES cells[14,15,16]. Several CpG islands are harbored in the Sox[2] locus, which cover and flank the Sox[2] gene. This suggests a possible role for CpG islands in Sox[2] regulation by attracting transcription factors for transcriptional initiation, or propagating transcriptional silencing via DNA methylation[17]. The Sox[2] promoter in ES cells is marked by permissive H3K4me[3] histone marks, while the surrounding CpG islands are bivalently marked, Official journal of the Cell Death Differentiation Association

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