Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect

Nizon, Mathilde; Laugel, Vincent; Flanigan, Kevin M.; Pastore, Matthew; Waldrop, Megan A.; Rosenfeld, Jill A.; Marom, Ronit; Xiao, Rui; Gerard, Amanda; Pichon, Olivier; Caignec, Cédric Le; Gérard, Marion; Dieterich, Klaus; Cho, Megan Truitt; McWalter, Kirsty; Hiatt, Susan M.; Thompson, Michelle L.; Bézieau, Stéphane; Wadley, Alexandrea; Wierenga, Klaas J.; Egly, Jean‐Marc; Isidor, Bertrand

doi:10.1038/s41436-019-0557-3

Cited by 27 publications

(24 citation statements)

References 41 publications

(46 reference statements)

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“…Therefore, another interpretation of the knockout results is that removing Med13 or Med13L may invoke a gene dosage-related phenotype. For example, recent studies found that MED13 or MED13L haploinsufficiency results in several overlapping, but not identical, developmental syndromes (41)(42)(43)(44)(45)(46). Therefore, transcriptional control by Med13 and Med13L may be exquisitely sensitive to gene copy number.…”

Section: Discussionmentioning

confidence: 99%

The extent of cyclin C promoter occupancy directs changes in stress-dependent transcription

Stieg

Cooper

Strich

2020

Journal of Biological Chemistry

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The Cdk8 kinase module (CKM) is a detachable Mediator subunit composed of cyclin C and one each of paralogs Cdk8/Cdk19, Med12/Med12L and Med13/Med13L. Our previous RNA-seq studies demonstrated that cyclin C represses a subset of hydrogen peroxide-induced genes under normal conditions, but is involved in activating other loci following stress. Here, we show that cyclin C directs this transcriptional re-programing through changes in its promoter occupancy. Following peroxide stress, cyclin C promoter occupancy increased for genes it activates while decreasing at loci it represses under normal conditions. Promoter occupancy of other CKM components generally mirrored cyclin C indicating that the CKM moves as a single unit. It has previously been shown that some cyclin C leaves the nucleus following cytotoxic stress to induce mitochondrial fragmentation and apoptosis. We observed that CKM integrity appeared compromised at a subset of repressed promoters suggesting a source of cyclin C that is targeted for nuclear release. Interestingly, mTOR inhibition induced a new pattern of cyclin C promoter occupancy indicating that this control is fine-tuned to the individual stress. Using inhibitors, we found that Cdk8 kinase activity is not required for CKM movement or repression but was necessary for full gene activation. In conclusion, this study revealed that different stress stimuli elicit specific changes in CKM promoter occupancy correlating to altered transcriptional outputs. Finally, although CKM components were recruited or expelled from promoters as a unit, heterogeneity was observed at individual promoters suggesting a mechanism to generate gene- and stress-specific responses.

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Section: Discussionmentioning

confidence: 99%

The extent of cyclin C promoter occupancy directs changes in stress-dependent transcription

Stieg

Cooper

Strich

2020

Journal of Biological Chemistry

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“…To find candidate genes that participate in osteoclastogenesis after treatment with myostatin, a CHIP assay was performed, and 20 genes that were clearly upregulated or downregulated were selected. These differentially expressed genes play important roles in inflammation ( Slominski et al, 2020 ), calcium channels ( Fenninger et al, 2019 ), transcription ( Nizon et al, 2019 ; Gura et al, 2020 ), cell differentiation ( Gobbi et al, 2019 ), and cell apoptosis ( Morris et al, 2020 ). II9, for example, is critical for mast cell-driven diseases ( Abdul Qayum et al, 2019 ), while Htatip2 can regulate the cell cycle and promote cell apoptosis ( Zhao et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Myostatin Promotes Osteoclastogenesis by Regulating Ccdc50 Gene Expression and RANKL-Induced NF-κB and MAPK Pathways

et al. 2020

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Myostatin is a crucial cytokine that is widely present in skeletal muscle and that negatively regulates the growth and development of muscle cells. Recent research has shown that myostatin might play an essential role in bone metabolism. In RAW264.7 cells and bone marrow monocytes (BMMCs), myostatin activates the expression of the II type receptor ActR II B. Here, we report that myostatin significantly promoted RANKL/M-CSF-induced osteoclastogenesis and activated NF-κB and MAPK pathways in vitro via the Ccdc50 gene. Overexpression of myostatin promoted osteoclastogenesis and osteoclastogenesis-related markers including c-Src, MMP9, CTR, CK, and NFATc1. Specifically, myostatin increased the phosphorylation of Smad2, which led to the activation of NF-κB and MAPK pathways to activate osteoclastogenesis. Ccdc50 was identified as a gene whose expression was highly decreased in osteoclastogenesis upon myostatin treatment, and it could inhibit the function of myostatin in osteoclastogenesis by blocking NF-κB and MAPKs pathways. Our study indicates that myostatin is a promising candidate target for inhibiting RANKL-mediated osteoclastogenesis and might participate in therapy for osteoporosis, and that the Ccdc50 gene plays a significant role in the regulatory process.

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“…Therefore, another interpretation of the knockout results is that removing Med13 or Med13L may invoke a gene dosage-related phenotype. For example, recent studies found that MED13 or MED13L haploinsufficiency results in several overlapping, but not identical, developmental syndromes (40)(41)(42)(43)(44)(45). Therefore, transcriptional control by Med13 and Med13L may be exquisitely sensitive to gene copy number.…”

Section: Discussionmentioning

confidence: 99%

Cyclin C promoter occupancy directs changes in stress-dependent transcription

Stieg

Cooper

Strich

2020

Preprint

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The Cdk8 kinase module (CKM) is a detachable Mediator subunit composed of cyclin C, and one each of paralogs Cdk8/Cdk19, Med12/Med12L and Med13/Med13L. In addition to regulating transcription, a portion of cyclin C also leaves the nucleus following cytotoxic stress to induce mitochondrial fragmentation and apoptosis. Our previous RNA-seq studies demonstrated that cyclin C represses a subset of hydrogen peroxide-induced genes under normal conditions, while also being required for the full induction of other loci following stress. Here, we show that cyclin C directs this transcriptional re-programing through changes in its promoter occupancy. Following peroxide stress, cyclin C promoter occupancy increased for genes it activates while decreasing at loci it represses under normal conditions. Promoter occupancy of other CKM components generally mirrored cyclin C indicating that the CKM moves as a single unit. However, CKM integrity appeared compromised at a subset of repressed promoters suggesting a source of cyclin C that is targeted for nuclear release. Interestingly, mTOR inhibition induced a new pattern of cyclin C promoter occupancy indicating that this control is fine-tuned to the individual stress. Using inhibitors, we found that Cdk8 kinase activity is not required for CKM movement or repression but was necessary for full gene activation. In conclusion, this study revealed that different stress stimuli elicit specific changes in CKM promoter occupancy correlating to altered transcriptional outputs. Finally, although CKM components were recruited or expelled from promoters as a unit, heterogeneity was observed at individual promoters suggesting a mechanism to generate gene- and stress-specific responses.

show abstract

Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect

Cited by 27 publications

References 41 publications

The extent of cyclin C promoter occupancy directs changes in stress-dependent transcription

The extent of cyclin C promoter occupancy directs changes in stress-dependent transcription

Myostatin Promotes Osteoclastogenesis by Regulating Ccdc50 Gene Expression and RANKL-Induced NF-κB and MAPK Pathways

Cyclin C promoter occupancy directs changes in stress-dependent transcription

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