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Sequence-specific RNA recognition drives Restrictor-mediated termination of extragenic transcription [ChIP-Seq]

ABSTRACT: Mammalian genomes harbour hundreds of thousands of RNA Polymerase II (Pol II) landing pads, enhancers and promoters, from which transcription can initiate bidirectionally. Nevertheless, processive transcription is largely restricted to the small gene-containing fraction of the genome. A highly conserved and essential metazoan complex, Restrictor, composed of WDR82 and ZC3H4, restrains processive Pol II activity at thousands of extragenic transcription units, thus representing a critical enforcer of genome utilization. However, because of the widespread recruitment of Restrictor to both genic and non-genic transcription sites, the identification of the mechanistic basis for its exquisite selectivity for extragenic transcription has remained elusive thus far. Here, we show that while WDR82 tethers Restrictor to sites of transcription initiation, the three C3H1-type zinc fingers of ZC3H4 make sequence-specific interactions with short motifs selectively enriched at the 5’ end of extragenic transcripts, with such interactions being required for transcription termination. Hence, while Restrictor recruitment relies on WDR82-dependent tethering to the initiating Pol II, its selectivity mainly arises from sequence-specific RNA recognition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE300318 | GEO | 2026/03/09

REPOSITORIES: GEO

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Sequence-specific RNA recognition drives Restrictor-mediated termination of extragenic transcription [HeLa__4sU-RNAseq]

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Restrictor synergizes with Symplekin and PNUTS to terminate extragenic transcription

Project description:Transcription termination pathways mitigate the detrimental consequences of unscheduled promiscuous initiation occurring at hundreds of thousands of genomic cis-regulatory elements. The Restrictor complex, composed of the Pol II-interacting protein WDR82 and the RNA-binding protein ZC3H4, suppresses processive transcription at thousands of extragenic sites in mammalian genomes. Restrictor-driven termination does not involve nascent RNA cleavage and its interplay with other termination machineries is unclear. Here we show that efficient termination at Restrictor-controlled extragenic transcription units involves the recruitment of the protein phosphatase 1 (PP1) regulatory subunit PNUTS, a negative regulator of the Spt5 elongation factor, and Symplekin, a protein associated with RNA cleavage complexes but also involved in cleavage-independent and phosphatase-dependent termination of non-coding RNAs in yeast. PNUTS and Symplekin act synergistically with, but independently from Restrictor to dampen processive extragenic transcription. Moreover, the presence of limiting nuclear levels of Symplekin imposes a competition for its recruitment among multiple transcription termination machineries, resulting in mutual regulatory interactions. Hence, by synergizing with Restrictor, Symplekin and PNUTS enable efficient termination of processive, long-range extragenic transcription.

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PP1/PNUTS phosphatase binds the restrictor complex and stimulates RNA pol II transcription termination

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