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Human GW182 Paralogs are the Central Organizers for RNA-Mediated Control of Transcription

ABSTRACT: In the cytoplasm, small RNAs can control mammalian translation by regulating the stability of mRNA. In the nucleus, small RNAs can also control transcription and splicing. The mechanisms for RNA-mediated nuclear regulation are not understood and remain controversial, hindering the effective application of nuclear RNAi and blinding investigation of its natural regulatory roles. Here we reveal that the human GW182 paralogs TNRC6A/B/C are central organizing factors critical to RNA-mediated transcriptional activation. Mass spectrometry of purified nuclear lysates followed by experimental validation demonstrates that TNRC6A interacts with proteins involved in protein degradation, RNAi, the CCR4-NOT complex, the mediator complex, and histone modifying complexes. Functional analysis implicates TNRC6A, NAT10, MED14, and WDR5 in RNA-mediated transcriptional activation. These findings describe protein complexes capable of bridging RNA-mediated sequence-specific recognition of noncoding RNA transcripts with the regulation of gene transcription.

INSTRUMENT(S): q exactive HF, orbitrap fusion lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: David R. Corey

PROVIDER: MSV000081227 | MassIVE | Fri Jul 07 12:02:00 BST 2017

REPOSITORIES: MassIVE

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Project description:Small RNA-guided chromatin silencing, also referred to as nuclear RNAi, plays an essential role in genome surveillance in eukaryotes and provides a unique paradigm to explore the complexity in RNA-mediated chromatin regulation and transgenerational epigenetics. A well-recognized paradox in this research area is that transcription of the target loci is necessary for the initiation and maintenance of the silencing at the same loci. How the two opposing activities (transcriptional activation and repression) are coordinated during animal development is poorly understood. To resolve this gap, we took single-molecule RNA imaging, deep-sequencing, and genetic approaches towards delineating the developmental regulation and subcellular localization of RNA transcripts of two exemplary endogenous germline nuclear RNAi targets in C. elegans, Cer3 and Cer8 LTR retrotransposons. By examining the wild type and a collection of mutant strains, we found that transcription and silencing cycle of Cer3 and Cer8 is tightly coupled with the early embryogenesis and germline mitotic and meiotic cell cycles. Strikingly, Cer3 and Cer8 transcripts are exclusively localized in the nuclei of germ cells in both wild type and germline nuclear RNAi-defective mutant animals. RNA-sequencing analysis found that this nuclear enrichment feature is a general feature for the endogenous targets of the germline nuclear RNAi pathway. In addition, the germline and somatic repressions of Cer3 have different genetic requirement for the three H3K9 histone methyltransferases, MET-2, SET-25, and SET-32, in conjunction with the nuclear Argonaute protein WAGO-9/HRDE-1. These results provide a first comprehensive cellular and developmental characterization of the nuclear RNAi-targeted endogenous targets throughout animal reproductive cycle. Altogether, these results support a model in which (1) both the transcriptional activation and repression steps of the germline nuclear RNAi pathway are tightly coupled with animal development, (2) the endogenous targets exhibit a hallmark of nuclear enrichment of their transcripts, and (3) different heterochromatin enzymes play distinct roles in somatic and germline silencing of the endogenous targets.

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Human GW182 Paralogs are the Central Organizers for RNA-Mediated Control of Transcription

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