Integrator mediates the biogenesis of enhancer RNAs

Lai, Fang; Gardini, Alessandro; Zhang, Anda; Shiekhattar, Ramin

doi:10.1038/nature14906

Cited by 274 publications

(298 citation statements)

References 31 publications

(42 reference statements)

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“…We envision that, in addition to determining the fate of coding and noncoding RNAs, 3′-end processing and termination factors serve to specify certain genomic regions including retroelements and repeat loci as preferential targets of heterochromatin assembly. Given that 3′-end processing factors leading to transcription termination also play a crucial role in the regulation of gene expression in Arabidopsis, Caenorhabditis elegans, and mammals (42,44,(63)(64)(65)(66), our results have important implications for understanding gene-regulatory mechanisms in metazoans.…”

Section: Discussionmentioning

confidence: 99%

Conserved factor Dhp1/Rat1/Xrn2 triggers premature transcription termination and nucleates heterochromatin to promote gene silencing

Chalamcharla

Folco

Dhakshnamoorthy

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cotranscriptional RNA processing and surveillance factors mediate heterochromatin formation in diverse eukaryotes. In fission yeast, RNAi machinery and RNA elimination factors including the Mtl1-Red1 core and the exosome are involved in facultative heterochromatin assembly; however, the exact mechanisms remain unclear. Here we show that RNA elimination factors cooperate with the conserved exoribonuclease Dhp1/Rat1/Xrn2, which couples premRNA 3′-end processing to transcription termination, to promote premature termination and facultative heterochromatin formation at meiotic genes. We also find that Dhp1 is critical for RNAi-mediated heterochromatin assembly at retroelements and regulated gene loci and facilitates the formation of constitutive heterochromatin at centromeric and mating-type loci. Remarkably, our results reveal that Dhp1 interacts with the Clr4/Suv39h methyltransferase complex and acts directly to nucleate heterochromatin. Our work uncovers a previously unidentified role for 3′-end processing and transcription termination machinery in gene silencing through premature termination and suggests that noncanonical transcription termination by Dhp1 and RNA elimination factors is linked to heterochromatin assembly. These findings have important implications for understanding silencing mechanisms targeting genes and repeat elements in higher eukaryotes.heterochromatin | Dhp1/Xrn2 | S. pombe | transcription termination

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Section: Discussionmentioning

confidence: 99%

Conserved factor Dhp1/Rat1/Xrn2 triggers premature transcription termination and nucleates heterochromatin to promote gene silencing

Chalamcharla

Folco

Dhakshnamoorthy

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…However, deficiency of Pou5f3 and Ints6 also causes defects in epiboly, as seen in split top mutants. Pou5f3 and Runx2b are transcription factors, and Ints6 is a component of the Integrator complex that acts in 3′ end processing of RNA and in other processes (Baillat et al, 2005;Lai et al, 2015). Interestingly, Lnx2b is a ubiquitin ligase that binds and ubiquitinates Bozozok, regulating its stability (Ro and Dawid, 2009).…”

Section: Discussion Ctsba Endopeptidase Function In Developmentmentioning

confidence: 99%

Split top: A maternal cathepsin B that regulates dorsoventral patterning and morphogenesis

et al. 2016

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The vertebrate embryonic dorsoventral axis is established and patterned by Wnt and bone morphogenetic protein (BMP) signaling pathways, respectively. Whereas Wnt signaling establishes the dorsal side of the embryo and induces the dorsal organizer, a BMP signaling gradient patterns tissues along the dorsoventral axis. Early Wnt signaling is provided maternally, whereas BMP ligand expression in the zebrafish is zygotic, but regulated by maternal factors. Concomitant with BMP activity patterning dorsoventral axial tissues, the embryo also undergoes dramatic morphogenetic processes, including the cell movements of gastrulation, epiboly and dorsal convergence. Although the zygotic regulation of these cell migration processes is increasingly understood, far less is known of the maternal regulators of these processes. Similarly, the maternal regulation of dorsoventral patterning, and in particular the maternal control of ventral tissue specification, is poorly understood. We identified split top, a recessive maternal-effect zebrafish mutant that disrupts embryonic patterning upstream of endogenous BMP signaling. Embryos from split top mutant females exhibit a dorsalized embryonic axis, which can be rescued by BMP misexpression or by derepressing endogenous BMP signaling. In addition to dorsoventral patterning defects, split top mutants display morphogenesis defects that are both BMP dependent and independent. These morphogenesis defects include incomplete dorsal convergence, delayed epiboly progression and an early lysis phenotype during gastrula stages. The latter two morphogenesis defects are associated with disruption of the actin and microtubule cytoskeleton within the yolk cell and defects in the outer enveloping cell layer, which are both known mediators of epiboly movements. Through chromosomal mapping and RNA sequencing analysis, we identified the lysosomal endopeptidase cathepsin Ba (ctsba) as the gene deficient in split top embryos. Our results identify a novel role for Ctsba in morphogenesis and expand our understanding of the maternal regulation of dorsoventral patterning.

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“…RNA-seq and ChIP-seq were performed as described previously (Gardini et al 2014;Lai et al 2015). Briefly, NEBNext Ultra RNA and the ChIP-seq library preparation kit for Illumina (New England Biolabs, E7420 and E6240) were used to prepare the sequencing library.…”

Section: Rna-seq and Chip-seqmentioning

confidence: 99%

“…We demonstrated recently that Integrator is also directed to enhancers, where it facilitates transcription of enhancer RNAs (eRNAs) and mediates their 3 ′ end processing (Lai et al 2015). The functions of Integrator at IEGs are clearly dictated by growth factor stimulation; however, the signaling pathways that converge on Integrator have yet to be defined.…”

mentioning

confidence: 99%

Integrator orchestrates RAS/ERK1/2 signaling transcriptional programs

et al. 2017

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Activating mutations in the mitogen-activated protein kinase (MAPK) cascade, also known as the RAS-MEK-extracellular signal-related kinase (ERK1/2) pathway, are an underlying cause of >70% of human cancers. While great strides have been made toward elucidating the cytoplasmic components of MAPK signaling, the key downstream coactivators that coordinate the transcriptional response have not been fully illustrated. Here, we demonstrate that the MAPK transcriptional response in human cells is funneled through Integrator, an RNA polymerase II-associated complex. Integrator depletion diminishes ERK1/2 transcriptional responsiveness and cellular growth in human cancers harboring activating mutations in MAPK signaling. Pharmacological inhibition of the MAPK pathway abrogates the stimulus-dependent recruitment of Integrator at immediate early genes and their enhancers. Following epidermal growth factor (EGF) stimulation, activated ERK1/2 is recruited to immediate early genes and phosphorylates INTS11, the catalytic subunit of Integrator. Importantly, in contrast to the broad effects of Integrator knockdown on MAPK responsiveness, depletion of a number of critical subunits of the coactivator complex Mediator alters only a few MAPK-responsive genes. Finally, human cancers with activating mutations in the MAPK cascade, rendered resistant to targeted therapies, display diminished growth following depletion of Integrator. We propose Integrator as a crucial transcriptional coactivator in MAPK signaling, which could serve as a downstream therapeutic target for cancer treatment.

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Integrator mediates the biogenesis of enhancer RNAs

Cited by 274 publications

References 31 publications

Conserved factor Dhp1/Rat1/Xrn2 triggers premature transcription termination and nucleates heterochromatin to promote gene silencing

Conserved factor Dhp1/Rat1/Xrn2 triggers premature transcription termination and nucleates heterochromatin to promote gene silencing

Split top: A maternal cathepsin B that regulates dorsoventral patterning and morphogenesis

Integrator orchestrates RAS/ERK1/2 signaling transcriptional programs

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