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The nuclear pore-associated TREX-2 complex employs the Mediator Med31 submodule as a docking site to regulate gene expression

ABSTRACT: Nuclear pore complexes (NPCs) influence gene expression besides their established function in nuclear transport. The TREX-2 complex localizes to the NPC basket and affects gene-NPC interactions, transcription and mRNA export. How TREX-2 regulates the gene expression machinery is unknown. Here, we show that TREX-2 interacts with the Mediator complex, an essential regulator of RNA Polymerase (Pol) II. Structural and biochemical studies identify a conserved region on TREX-2, which directly binds the Mediator Med31/Med7N submodule. TREX-2 regulates assembly of Mediator with its Cdk8 kinase and is required for recruitment and site-specific phosphorylation of Pol II. Transcriptome and phenotypic profiling confirm that TREX-2 and Med31 are functionally interdependent. TREX-2 additionally uses its Mediator-interacting surface to regulate mRNA export suggesting a mechanism for coupling transcription initiation and early steps of mRNA processing at the Mediator level. In sum, we provide insight into how NPC-associated adaptor complexes can access the core transcription machinery. RNAseq was performed from WT, sac3∆, cdk8∆ and Sac3 R288D mutant cells. For each strain triplicates were analyzed. WT strain was sac3∆ transformed with pRS315 SAC3 WT

ORGANISM(S): Saccharomyces cerevisiae

SUBMITTER: Alwin Koehler

PROVIDER: E-GEOD-67431 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The nuclear pore-associated TREX-2 complex employs the Mediator Med31 submodule as a docking site to regulate gene expression

Project description:Nuclear pore complexes (NPCs) influence gene expression besides their established function in nuclear transport. The TREX-2 complex localizes to the NPC basket and affects gene-NPC interactions, transcription and mRNA export. How TREX-2 regulates the gene expression machinery is unknown. Here, we show that TREX-2 interacts with the Mediator complex, an essential regulator of RNA Polymerase (Pol) II. Structural and biochemical studies identify a conserved region on TREX-2, which directly binds the Mediator Med31/Med7N submodule. TREX-2 regulates assembly of Mediator with its Cdk8 kinase and is required for recruitment and site-specific phosphorylation of Pol II. Transcriptome and phenotypic profiling confirm that TREX-2 and Med31 are functionally interdependent. TREX-2 additionally uses its Mediator-interacting surface to regulate mRNA export suggesting a mechanism for coupling transcription initiation and early steps of mRNA processing at the Mediator level. In sum, we provide insight into how NPC-associated adaptor complexes can access the core transcription machinery.

2015-08-27 | GSE67431 | GEO

ChIP-chip data of Thp1-Flag and Sac3-Flag in wild-type cells, and Rrm3-Flag in sac3∆ and thp1∆ cells

2014-10-08 | GSE56700 | GEO

Expression data from Saccharomyces cerevisiae strains deleted for the THSC/TREX-2 subunits Thp1, Sac3 and Sus1

2014-10-08 | GSE56702 | GEO

Expression data from Saccharomyces cerevisiae strains deleted for the THSC/TREX-2 subunits Thp1, Sac3 and Sus1

2014-10-08 | E-GEOD-56702 | biostudies-arrayexpress

ChIP-chip data of Thp1-Flag and Sac3-Flag in wild-type cells, and Rrm3-Flag in sac3M-bM-^HM-^F and thp1M-bM-^HM-^F cells

Project description:Transcription is a major obstacle for replication fork progression and a cause of genome instability. Such instability increases in mutants with a suboptimal assembly of the nascent messenger ribonucleo-protein particle (mRNP), as THO/TREX and the NPC-associated THSC/TREX-2 complex. Here we show that yeast sac3M-bM-^HM-^F and thp1M-bM-^HM-^F cells accumulate genome-wide replication obstacles as determined by the distribution of the Rrm3 helicase. Such obstacles preferentially occur at long and highly expressed genes, to which Sac3 and its interacting partner Thp1 are preferentially bound in wild-type cells. ChIP-chip studies were perfomed with antibodies against Flag-tagged Thp1 and Sac3 proteins in wild-type cells of the yeast S. Cerevisiae, as well as Flag-tagged Rrm3 protein in sac3M-bM-^HM-^F and thp1M-bM-^HM-^F cells that were compared with Rrm3 in wild-type cells from Santos-Pereira et al., 2013 (accession number GSE50185).

2014-10-08 | E-GEOD-56700 | biostudies-arrayexpress

Colorectal Cancer Organoid Proteomics

Project description:Cyclin Dependent Kinases CDK8 and CDK19 (Mediator kinase) are regulatory components of the Mediator complex, a highly conserved complex that fine tunes transcriptional output. While Mediator kinase has been implicated in the transcriptional control of key pathways necessary for development and growth, its function in vivo has not been well described. Herein, we report the consequences of complete ablation of both Cdk8/19 on tissue homeostasis. We show that intestinal epithelial specific deletion of Mediator kinase leads to a distinct defect in secretory progenitor differentiation with broad loss of the intestinal secretory cell types. Using a phospho-proteogenomic approach, we show that the Cdk8/19 kinase module interacts with and phosphorylates components of the chromatin remodeling complex Swi/Snf in intestinal epithelial cells. Genomic localisation of Swi/Snf and Mediator shows Cdk8/19-dependent genomic binding at distinct super-enhancer loci within key lineage specification genes, including the master regulator of secretory differentiation ATOH1. Using CRISPRi/CRISPRa, we identify a distinct Mediator-Swi/Snf bound enhancer element that is necessary and sufficient for ATOH1 expression in a Mediator-kinase dependent manner. As such, these studies uncover a newly described transcriptional mechanism of ATOH1-dependent intestinal cell specification that is dependent on the coordinated interaction of the chromatin remodeling complex Swi/Snf and Mediator complex.

2023-03-11 | PXD030256 | Pride

Transcription profiling by array of yeast wild type and delta Sro9 cells

Project description:The influence of Sro9 on steady-state levels of a specific set of mRNAs in yeast was investigated. This was assessed using whole genome expression profiling of delta Sro9 in comparison to wild-type cells.

2010-05-01 | E-MEXP-2678 | biostudies-arrayexpress

The m 6 A-methylase complex recruits TREX and regulates mRNA export.

Project description:N6-methyladenosine (m6A) is the most abundant internal modification of eukaryotic mRNA. This modification has previously been shown to alter the export kinetics for mRNAs though the molecular details surrounding this phenomenon remain poorly understood. Here we show that the m6A complex (WTAP, KIAA1429, METTL3/14) drives recruitment of the TREX mRNA export complex onto m6A modified mRNAs and this process is essential for the efficient export of certain mRNAs. Depletion of the core m6A complex leads to loss of TREX from mRNAs which undergo the m6A modification. We show that TREX stimulates recruitment of the m6A reader protein YTHDC1 to the mRNP and the m6A complex influences the interaction of TREX with YTHDC1. We suggest that m6A acts as a surrogate for other TREX recruitment mechanisms such as splicing and 5’ capping, in long internal and final exons which may otherwise be devoid of this essential complex for mRNA export.

2018-10-03 | GSE111878 | GEO

TREX tetramer disruption alters RNA processing necessary for corticogenesis in THOC6 Intellectual Disability Syndrome

Project description:THOC6 is the genetic basis of autosomal recessive THOC6 Intellectual Disability Syndrome (TIDS). THOC6 is critical for mammalian Transcription Export complex (TREX) tetramer formation, which is composed of four six-subunit THO monomers. The TREX tetramer facilitates mammalian RNA processing, in addition to the nuclear mRNA export functions of the TREX dimer conserved through yeast. Human and mouse TIDS model systems revealed novel THOC6-dependent, species-specific TREX tetramer functions. Germline biallelic Thoc6 loss-of-function (LOF) variants result in mouse embryonic lethality. Biallelic THOC6 LOF variants do not alter the expression of TREX dimer component proteins in human cells, but reduced binding affinity to ALYREF implicates impaired TREX tetramer formation. Defects in RNA nuclear export functions were not detected in biallelic THOC6 LOF human neural cells. Instead, mis-splicing was detected in human and mouse neural tissue, revealing novel THOC6-mediated TREX coordination of mRNA processing. We demonstrate that THOC6 is required for regulation of key signaling pathways in human corticogenesis that dictate the transition from proliferative to neurogenic divisions, developmental biology implicated in TIDS neuropathology.

2023-10-17 | GSE245121 | GEO

Expression data in HeLa S3 cells transfected with control-, UAP56- or URH49-siRNA

Project description:Nuclear export of mRNA is an essential process for eukaryotic gene expression. TREX complex couples the gene expression from transcription and splicing to mRNA export. Sub2, a core component of TREX complex in yeast is diversified to two closely related RNA helicases, UAP56 and URH49 in human.UAP56 and URH49 are required for bulk poly (A)+ RNA export but their target genes are quite different. In conclusion, UAP56 and URH49 have a different function in vivo despite the highly similarity. Cytoplasmic RNA was prepared in HeLa cells transfected with control-, UAP56- and URH49-siRNA and analyzed by gene expression array.

2010-08-15 | E-GEOD-18173 | biostudies-arrayexpress

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