Mediator Roles Going Beyond Transcription

André, Kévin M.; Sipos, Eliet H.; Soutourina, Julie

doi:10.1016/j.tig.2020.08.015

Cited by 21 publications

(16 citation statements)

References 85 publications

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“…Its regulation involves epigenetic modifications of chromatin to allow the access of the transcriptional machinery to the DNA, the subsequent processing of the pre-mRNAs and the translation of the specific mRNAs into proteins. These mechanisms are finely coordinated and interconnected, and involve the activity of epigenetic modulators, transcription and splicing factors and post-translational modifiers ( 59 , 60 ) which in many cases are essential to preserve cell identity and cell survival. In the last years, our laboratory has discovered that the splicing regulator SLU7 is required to preserve the mature and functional hepatic transcriptome ( 16 ) and we have uncovered its crucial role to secure correct cell division, preventing the induction of genome instability and cell cycle arrest ( 17 ).…”

Section: Discussionmentioning

confidence: 99%

The splicing regulator SLU7 is required to preserve DNMT1 protein stability and DNA methylation

Recalde

Gárate-Rascón

Elizalde

et al. 2021

Nucleic Acids Research

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Gene expression is finely and dynamically controlled through the tightly coordinated and interconnected activity of epigenetic modulators, transcription and splicing factors and post-translational modifiers. We have recently identified the splicing factor SLU7 as essential for maintaining liver cell identity and genome integrity and for securing cell division both trough transcriptional and splicing mechanisms. Now we uncover a new function of SLU7 controlling gene expression at the epigenetic level. We show that SLU7 is required to secure DNMT1 protein stability and a correct DNA methylation. We demonstrate that SLU7 is part in the chromatome of the protein complex implicated in DNA methylation maintenance interacting with and controlling the integrity of DNMT1, its adaptor protein UHRF1 and the histone methyl-transferase G9a at the chromatin level. Mechanistically, we found that SLU7 assures DNMT1 stability preventing its acetylation and degradation by facilitating its interaction with HDAC1 and the desubiquitinase USP7. Importantly, we demonstrate that this DNMT1 dependency on SLU7 occurs in a large panel of proliferating cell lines of different origins and in in vivo models of liver proliferation. Overall, our results uncover a novel and non-redundant role of SLU7 in DNA methylation and present SLU7 as a holistic regulator of gene expression.

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Section: Discussionmentioning

confidence: 99%

The splicing regulator SLU7 is required to preserve DNMT1 protein stability and DNA methylation

Recalde

Gárate-Rascón

Elizalde

et al. 2021

Nucleic Acids Research

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“…Mammalian MED is a large multiprotein complex that plays a key regulatory role in the RNA polymerase II transcriptional process. As mentioned, it was first discovered in yeast as a factor required for activator-dependent transcription of genes but is clear that is involved in every step of transcription by RNA polymerase II including preinitiation complex formation, transcription activation, initiation, promoter clearance, elongation, splicing, gene looping and termination [ 47 , 48 ]. Metazoan MED is composed of at least 30 different subunits named MEDs (from 1–30) and it is highly conserved among all eukaryotes [ 47 ].…”

Section: Mediator and Breast Cancermentioning

confidence: 99%

“…MED12 C terminus ends in an odd-paired (OPA) motif domain. Both of these domains are crucial for the regulatory function of MED12, since they serve as binding sites for several transcription factors [ 48 ]. The protein also has a LCEWAV motif towards its N terminus, whose function remains unclear yet [ 65 ] ( Figure 4 B).…”

Section: Mediator and Breast Cancermentioning

confidence: 99%

Role of the Mediator Complex and MicroRNAs in Breast Cancer Etiology

Maldonado

Morales-Pison

Urbina

et al. 2022

Genes

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Transcriptional coactivators play a key role in RNA polymerase II transcription and gene regulation. One of the most important transcriptional coactivators is the Mediator (MED) complex, which is an evolutionary conserved large multiprotein complex. MED transduces the signal between DNA-bound transcriptional activators (gene-specific transcription factors) to the RNA polymerase II transcription machinery to activate transcription. It is known that MED plays an essential role in ER-mediated gene expression mainly through the MED1 subunit, since estrogen receptor (ER) can interact with MED1 by specific protein–protein interactions; therefore, MED1 plays a fundamental role in ER-positive breast cancer (BC) etiology. Additionally, other MED subunits also play a role in BC etiology. On the other hand, microRNAs (miRNAs) are a family of small non-coding RNAs, which can regulate gene expression at the post-transcriptional level by binding in a sequence-specific fashion at the 3′ UTR of the messenger RNA. The miRNAs are also important factors that influence oncogenic signaling in BC by acting as both tumor suppressors and oncogenes. Moreover, miRNAs are involved in endocrine therapy resistance of BC, specifically to tamoxifen, a drug that is used to target ER signaling. In metazoans, very little is known about the transcriptional regulation of miRNA by the MED complex and less about the transcriptional regulation of miRNAs involved in BC initiation and progression. Recently, it has been shown that MED1 is able to regulate the transcription of the ER-dependent miR-191/425 cluster promoting BC cell proliferation and migration. In this review, we will discuss the role of MED1 transcriptional coactivator in the etiology of BC and in endocrine therapy-resistance of BC and also the contribution of other MED subunits to BC development, progression and metastasis. Lastly, we identified miRNAs that potentially can regulate the expression of MED subunits.

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“…The Mediator complex interacts with different TFs and is implicated in almost every aspect of transcription regulation [reviewed by Jeronimo and Robert (2017) ], chromatin architecture [reviewed by Andre et al (2021) ], and DNA repair ( Soutourina and Werner, 2014 ). Due to its many functions, Mediator is often associated with cancer and developmental disease ( Schiano et al, 2014 ; Yin and Wang, 2014 ).…”

Section: Mediator Complexmentioning

confidence: 99%

Transcription Pause and Escape in Neurodevelopmental Disorders

2022

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Transcription pause-release is an important, highly regulated step in the control of gene expression. Modulated by various factors, it enables signal integration and fine-tuning of transcriptional responses. Mutations in regulators of pause-release have been identified in a range of neurodevelopmental disorders that have several common features affecting multiple organ systems. This review summarizes current knowledge on this novel subclass of disorders, including an overview of clinical features, mechanistic details, and insight into the relevant neurodevelopmental processes.

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Mediator Roles Going Beyond Transcription

Cited by 21 publications

References 85 publications

The splicing regulator SLU7 is required to preserve DNMT1 protein stability and DNA methylation

The splicing regulator SLU7 is required to preserve DNMT1 protein stability and DNA methylation

Role of the Mediator Complex and MicroRNAs in Breast Cancer Etiology

Transcription Pause and Escape in Neurodevelopmental Disorders

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