Mediator's Kinase Module: A Modular Regulator of Cell Fate

Straub, Joseph; Venigalla, Sree; Newman, Jamie J.

doi:10.1089/scd.2020.0164

Cited by 6 publications

(7 citation statements)

References 132 publications

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“…Mediator functions as a bridge between cell type-specific transcription factors and the transcriptional machinery. As such, Mediator complex, and specifically MED12, is increasingly found to have an important role in the regulation of (super-)enhancers [ 1 ]. Super-enhancers are clustered enhancers whose combined influence allows them to drive high levels of gene expression.…”

Section: Med12 Regulates Gene Expression By Binding To (Super-)enhancers and Ncrnamentioning

confidence: 99%

“…So far, studies looking at X-inactivation patterns in blood or fibroblast cells found no correlation between XCI skewing and phenotype severity. However, no studies have looked at XCI in tissues relevant to the pathology of neurodevelopmental disorders, such as brain tissues [ 1 , 2 , 39 ]. This is unfortunate, as we deem it likely that the difference in phenotypes observed for nonsense variants in females could be explained by differences in XCI patterns, where Hardikar patients have one healthy allele active in the brain, while patients suffering from neurodevelopmental disorders express the variant allele in neuronal tissue.…”

Section: Conclusion: a Question Of Causalitymentioning

confidence: 99%

“…We propose that future studies on the effects of variants involved in MED12 -related disorders should focus on answering these questions in a simple, disease-relevant cellular model. MED12 is known as an important factor in the regulation of enhancer and super enhancer functioning [ 1 ]. It regulates cell type-specific active enhancers through stimulation of active chromatin marks [ 2 , 40 ].…”

Section: Conclusion: a Question Of Causalitymentioning

confidence: 99%

“…MED12 is a member of the multi-protein Mediator complex. The Mediator complex is part of the preinitiation complex, and is involved in transcriptional regulation [ 1 ]. It functions as a switchboard, relaying signals from gene-specific regulatory proteins to RNA polymerase II, to regulate transcription initiation and transcription elongation [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

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MED12-Related (Neuro)Developmental Disorders: A Question of Causality

Plassche

Brouwer

2021

Genes

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MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and Ohdo syndrome, as well as non-syndromic intellectual disability (ID) in hemizygous males. Recently, female patients with de novo missense variants and de novo protein truncating variants in MED12 were described, resulting in a clinical spectrum centered around ID and Hardikar syndrome without ID. The missense variants are found throughout MED12, whether they are inherited in hemizygous males or de novo in females. They can result in syndromic or nonsyndromic ID. The de novo nonsense variants resulting in Hardikar syndrome that is characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, are found more N-terminally, whereas the more C-terminally positioned variants are de novo protein truncating variants that cause a severe, syndromic phenotype consisting of ID, facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. This broad range of distinct phenotypes calls for a method to distinguish between pathogenic and non-pathogenic variants in MED12. We propose an isogenic iNeuron model to establish the unique gene expression patterns that are associated with the specific MED12 variants. The discovery of these patterns would help in future diagnostics and determine the causality of the MED12 variants.

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Section: Med12 Regulates Gene Expression By Binding To (Super-)enhancers and Ncrnamentioning

confidence: 99%

Section: Conclusion: a Question Of Causalitymentioning

confidence: 99%

Section: Conclusion: a Question Of Causalitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

MED12-Related (Neuro)Developmental Disorders: A Question of Causality

Plassche

Brouwer

2021

Genes

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“…One enhancer coactivator is the supramolecular Mediator complex, which serves as a signaling coordinator between transcriptional machinery and RNAPII through modulating subunit composition (22,23). Mediator is assembled as four subcomplexes referred to as "head", "middle" "tail" and "kinase" modules (24)(25)(26). While the head, middle and tail modules comprise the core Mediator, the fourth module reversibly interacts with the core through its Med13 subunit.…”

Section: Introductionmentioning

confidence: 99%

XLID Syndrome Gene Med12 Promotes Ig Isotype Switching through Chromatin Modification and Enhancer RNA regulation

Haque

Honjo

Begum

2022

Preprint

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The transcriptional co-activator Med12 regulates gene expression through the function of its kinase module and by interacting with the larger Mediator complex and associated RNA Polymerase II (RNAPII). Here, we show a kinase module-independent function of Med12 in antibody class switching recombination (CSR). Med12 is essential for IgH 3’ regulatory region (3’RR) or super-enhancer activation and functions with p300 and Jmjd6/Carm1 coactivator complexes. Med12 deficiency leads to a dramatic decrease in H3K27 acetylation and enhancer RNA (eRNA) transcription at 3’RR, with concomitant impairment of AID-induced DNA double strand breaks, long-range S-S synapse formation, and 3’RR-Eμ interaction. CRISPR/dCas9-mediated enhancer activation re-establishes the epigenomic and transcriptional hallmarks of the 3’RR super-enhancer, fully restoring Med12 depletion defects. Notably, we find that 3’RR derived eRNAs are critical for promoting proper S region epigenetic regulation, S-S synapse formation and recruitment of Med12 and AID to the IgH locus. We find specific X-Linked intellectual disability syndrome associated Med12 mutations are defective in both 3’RR eRNA transcription and CSR, suggesting B and neuronal cells may have cell-specific super-enhancer dysfunctions. We conclude Med12 is essential for IgH3’RR activation and eRNA transcription and plays a central role in AID-induced antibody gene diversification and genomic instability in B cells.

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Identification of two aberrant transcripts by RNA sequencing for a novel variant c.3354 + 5 G > A of MED12 in a Chinese girl with non-syndromic intellectual disability

Zhi

et al. 2022

Clinica Chimica Acta

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Mediator's Kinase Module: A Modular Regulator of Cell Fate

Cited by 6 publications

References 132 publications

MED12-Related (Neuro)Developmental Disorders: A Question of Causality

MED12-Related (Neuro)Developmental Disorders: A Question of Causality

XLID Syndrome Gene Med12 Promotes Ig Isotype Switching through Chromatin Modification and Enhancer RNA regulation

Identification of two aberrant transcripts by RNA sequencing for a novel variant c.3354 + 5 G > A of MED12 in a Chinese girl with non-syndromic intellectual disability

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