The Human Integrator Complex Facilitates Transcriptional Elongation by Endonucleolytic Cleavage of Nascent Transcripts.

Cell Reports
Felipe BeckedorffRamin Shiekhattar

Abstract

Transcription by RNA polymerase II (RNAPII) is pervasive in the human genome. However, the mechanisms controlling transcription at promoters and enhancers remain enigmatic. Here, we demonstrate that Integrator subunit 11 (INTS11), the catalytic subunit of the Integrator complex, regulates transcription at these loci through its endonuclease activity. Promoters of genes require INTS11 to cleave nascent transcripts associated with paused RNAPII and induce their premature termination in the proximity of the +1 nucleosome. The turnover of RNAPII permits the subsequent recruitment of an elongation-competent RNAPII complex, leading to productive elongation. In contrast, enhancers require INTS11 catalysis not to evict paused RNAPII but rather to terminate enhancer RNA transcription beyond the +1 nucleosome. These findings are supported by the differential occupancy of negative elongation factor (NELF), SPT5, and tyrosine-1-phosphorylated RNAPII. This study elucidates the role of Integrator in mediating transcriptional elongation at human promoters through the endonucleolytic cleavage of nascent transcripts and the dynamic turnover of RNAPII.

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Citations

Jan 2, 2021·Molecular Cell·Søren Lykke-AndersenTorben Heick Jensen
Feb 7, 2021·Molecular Cell·Moritz M Pfleiderer, Wojciech P Galej
Nov 20, 2020·Nature Reviews. Molecular Cell Biology·Melvin Noe GonzalezJesper Q Svejstrup
Dec 20, 2020·Current Opinion in Cell Biology·Nina KirsteinRamin Shiekhattar
Apr 30, 2021·ELife·Chris EstellSteven West
Jun 2, 2021·Biochemical Society Transactions·Søren Lykke-AndersenTorben Heick Jensen
Sep 24, 2021·Cell Communication and Signaling : CCS·Elena ShersherAnthony J Capobianco
Nov 4, 2021·Science Advances·Lucas Ferreira DasilvaRamin Shiekhattar

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Datasets Mentioned

BETA
GSE125535

Methods Mentioned

BETA
immunoprecipitation
PRO-seq
dissection
ChIP-seq
RNA-seq
smRNA-seq
PCR
ChIP

Software Mentioned

Clus
MATLAB
deepTools2
Homer annotatePeaks
BEDTools Window
Bedgraph
DAVID
Cutadapt
R
Doc

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