Nuclear Exosome Targeting Complex Core Factor Zcchc8 Regulates the Degradation of LINE1 RNA in Early Embryos and Embryonic Stem Cells

You Wu,Wenqiang Liu,Jiayu Chen,Shuaitong Liu,Mingzhu Wang,Lei Yang,Chuan Chen,Meijie Qi,Yiwen Xu,Zhibin Qiao,Rushuang Yan,Xiaochen Kou,Yanhong Zhao,Bin Shen,Jiqing Yin,Hong Wang,Yawei Gao,Shaorong Gao

doi:10.1016/j.celrep.2019.10.055

Abstract

The nuclear exosome targeting (NEXT) complex is responsible for specific nuclear RNA degradation in mammalian cells. However, its function in development remains unknown. Here, we find that the depletion of a central factor of the NEXT complex, Zcchc8, in mouse results in developmental defects, a shortened lifespan, and infertility. We find that Zcchc8-deficient embryonic stem cells (ESCs) exhibit proliferation abnormalities and reduced developmental potencies. Importantly, the transcripts of retrotransposon element LINE1 are found to be targeted by Zcchc8 and degraded by a Zcchc8-mediated mechanism. We further find that sustained expression of higher levels of LINE1 RNA is detected in maternal Zcchc8-depleted oocytes and embryos. Zcchc8-depleted oocytes show higher chromatin accessibility and developmental defects in both meiotic maturation and embryogenesis after fertilization. Collectively, our study defines Zcchc8-mediated RNA degradation as an important post-transcription regulation of LINE1 transcripts in early embryos and ESCs, which play vital roles in the pluripotency and early development.

Highlights

Nuclear RNA exosomes are responsible for eliminating redundant transcripts and maintaining the steady-state levels of diverse RNA species; in addition, they are highly conserved in eukaryotes
Zcchc8 Affects Blastocyst Formation In our recent study, we found that Zcchc8, a member of the complex, was abundant in the zygote and blastocyststage embryos on the basis of mass spectrometry analysis (Gao et al, 2017; Figure S1A)
RNA sequencing (RNA-seq) data showed that Zcchc8 mRNA was highly expressed in MII oocytes and zygotes and relatively downregulated after the two-cell stage (Liu et al, 2016; Figure S1A)

Summary

Introduction

Nuclear RNA exosomes are responsible for eliminating redundant transcripts and maintaining the steady-state levels of diverse RNA species; in addition, they are highly conserved in eukaryotes. The central role of nuclear exosomes includes RNA maturation, surveillance, and mRNA quality control during cell differentiation and development as well as in response to environmental cues (Bresson et al, 2017; McIver et al, 2016; Snee et al, 2016; Yap et al, 2012). The RNA helicase hMTR4/ SKIV2l2, the metazoan-specific Zn-knuckle protein ZCCHC8, and the RNA recognition motif (RRM)-containing protein RBM7 (Lubas et al, 2011) constitute the complex. Through an individual-nucleotide resolution UV cross-linking and immunoprecipitation (iCLIP) approach, RBM7 was found to target RNA polymerase II-derived RNAs, including pre-mRNAs and short-lived exosome substrates, such as promoter upstream transcripts (PROMPTs), enhancer RNAs (eRNAs), and 30extended products from small nuclear RNAs (snRNAs) and 30-extended small nucleolar RNAs (snoRNAs) derived from introns (Lubas et al, 2015).

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Conclusion