A first exon termination checkpoint preferentially suppresses extragenic transcription

Liv M I Austenaa, Viviana Piccolo, Marta Russo, Elena Prosperini, Sara Polletti, Danilo Polizzese, Serena Ghisletti, Iros Barozzi, Giuseppe R Diaferia, Gioacchino Natoli

Research output: Contribution to journalArticlepeer-review


Interactions between the splicing machinery and RNA polymerase II increase protein-coding gene transcription. Similarly, exons and splicing signals of enhancer-generated long noncoding RNAs (elncRNAs) augment enhancer activity. However, elncRNAs are inefficiently spliced, suggesting that, compared with protein-coding genes, they contain qualitatively different exons with a limited ability to drive splicing. We show here that the inefficiently spliced first exons of elncRNAs as well as promoter-antisense long noncoding RNAs (pa-lncRNAs) in human and mouse cells trigger a transcription termination checkpoint that requires WDR82, an RNA polymerase II-binding protein, and its RNA-binding partner of previously unknown function, ZC3H4. We propose that the first exons of elncRNAs and pa-lncRNAs are an intrinsic component of a regulatory mechanism that, on the one hand, maximizes the activity of these cis-regulatory elements by recruiting the splicing machinery and, on the other, contains elements that suppress pervasive extragenic transcription.

Original languageEnglish
Pages (from-to)337-346
Number of pages10
JournalNature Structural and Molecular Biology
Issue number4
Publication statusPublished - Apr 2021


  • Alternative Splicing/genetics
  • Animals
  • Chromosomal Proteins, Non-Histone/genetics
  • DNA-Binding Proteins/genetics
  • Exons/genetics
  • Humans
  • Mice
  • Promoter Regions, Genetic/genetics
  • RNA Polymerase II/genetics
  • RNA Splicing/genetics
  • RNA, Antisense/genetics
  • RNA, Long Noncoding/genetics
  • RNA, Messenger/genetics
  • Regulatory Sequences, Nucleic Acid/genetics
  • Transcription, Genetic


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