The role of Mediator and Little Elongation Complex in transcription termination

Hidehisa Takahashi,Hiroko Hirose,Junichi Yamamoto,Amol Ranjan,Joan Weliky Conaway ,Kazunori Sasaki,Haruo Suzuki ,Ichigaku Takigawa,Yuki Yamaguchi,Tomonori Hirose,Shigeo Sato,Masashi Watanabe,Kai Chen,Masaki Matsumoto,Shiyuan Chen,Mio Shibata,Ying Zhang,Midori Iida,Anita Saraf,Chieri Tomomori‐Sato ,Yanfeng He,Keiichi I Nakayama,Yutaka Suzuki,Satoshi Fujii,Michael P Washburn,Ryota Abe,Laurence Florens,Tadasuke Tsukiyama,Ronald C Conaway,Susumi Hatakeyama

doi:10.1038/s41467-020-14849-1

Abstract

Mediator is a coregulatory complex that regulates transcription of Pol II-dependent genes. Previously, we showed that human Mediator subunit MED26 plays a role in the recruitment of Super Elongation Complex (SEC) or Little Elongation Complex (LEC) to regulate the expression of certain genes. MED26 plays a role in recruiting SEC to protein-coding genes including c-myc and LEC to small nuclear RNA (snRNA) genes. However, how MED26 engages SEC or LEC to regulate distinct genes is unclear. Here, we provide evidence that MED26 recruits LEC to modulate transcription termination of non-polyadenylated transcripts including snRNAs and mRNAs encoding replication-dependent histone (RDH) at Cajal bodies. Our findings indicate that LEC recruited by MED26 promotes efficient transcription termination by Pol II through interaction with CBC-ARS2 and NELF/DSIF, and promotes 3′ end processing by enhancing recruitment of Integrator or Heat Labile Factor to snRNA or RDH genes, respectively.

Highlights

Mediator is a coregulatory complex that regulates transcription of polymerase II (Pol II)-dependent genes
We propose the model that (i) MED26 recruits Little Elongation Complex (LEC) to both replication-dependent histone (RDH) and small nuclear RNA (snRNA) genes in Cajal bodies, (ii) LEC binds to CBCA and negative elongation factor (NELF)/DRB sensitivity-inducing factor (DSIF) to inhibit Pol II readthrough past the normal termination sites on these genes, and (iii) LEC promotes the 3′-end processing of the RDH or snRNA genes by enhancing recruitment of heat-labile factor (HLF) or Integrator, respectively
We show evidence that both MED26 and LEC are present at snRNA and RDH genes

Summary

Introduction

Mediator is a coregulatory complex that regulates transcription of Pol II-dependent genes. MED26 plays a role in recruiting SEC to protein-coding genes including c-myc and LEC to small nuclear RNA (snRNA) genes. We provide evidence that MED26 recruits LEC to modulate transcription termination of non-polyadenylated transcripts including snRNAs and mRNAs encoding replication-dependent histone (RDH) at Cajal bodies. Our findings indicate that LEC recruited by MED26 promotes efficient transcription termination by Pol II through interaction with CBC-ARS2 and NELF/DSIF, and promotes 3′ end processing by enhancing recruitment of Integrator or Heat Labile Factor to snRNA or RDH genes, respectively. RNA genes produce polyadenylated messenger RNAs (mRNAs) after 3′-end processing, some genes, including snRNA and replication-dependent histone (RDH) genes, produce transcripts lacking poly(A) tails using a distinct 3′-end processing machinery. Recent evidence indicates that polyadenylated RDH transcripts contribute to the expression of RDH genes outside of S phase or in terminally differentiated, non-proliferating cells[11,12]

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Conclusion