Mediator Kinase Disruption in MED12-Mutant Uterine Fibroids From Hispanic Women of South Texas

Park, Min Ju; Shen, Hongxing; Kim, Nam Hee; Gao, Fangjian; Failor, Courtney; Knudtson, Jennifer F.; McLaughlin, Jessica; Halder, Sunil K.; Heikkinen, Tuomas; Vahteristo, Pia; Al-Hendy, Ayman; Schenken, Robert S.; Boyer, Thomas G.

doi:10.1210/jc.2018-00863

Cited by 25 publications

(28 citation statements)

References 39 publications

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“…Rather, our results show that changes in the CDK8 submodule cistrome are positively correlated with altered H3K27Ac, suggesting that altered CDK8 binding is more consistent with general changes in the enhancer landscape of leiomyoma cells. This aligns with recently published data in heterologous cell lines as well as leiomyoma tissue samples, which demonstrate that the presence of MED13 is a stabilizing protein in the submodule that compensates for any MED12 mutant-dependent interaction defect 51,52 . However, while MED13 may stabilize cyclin C-CDK8 chromatin binding in the presence of a mutation in MED12, it cannot compensate for the loss in kinase activity of the submodule.…”

Section: Discussionsupporting

confidence: 91%

Altered chromatin landscape and enhancer engagement underlie transcriptional dysregulation in MED12 mutant uterine leiomyomas

2020

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Uterine leiomyomas (fibroids) are a major source of gynecologic morbidity in reproductive age women and are characterized by the excessive deposition of a disorganized extracellular matrix, resulting in rigid benign tumors. Although down regulation of the transcription factor AP-1 is highly prevalent in leiomyomas, the functional consequence of AP-1 loss on gene transcription in uterine fibroids remains poorly understood. Using high-resolution ChIPsequencing, promoter capture Hi-C, and RNA-sequencing of matched normal and leiomyoma tissues, here we show that modified enhancer architecture is a major driver of transcriptional dysregulation in MED12 mutant uterine leiomyomas. Furthermore, modifications in enhancer architecture are driven by the depletion of AP-1 occupancy on chromatin. Silencing of AP-1 subunits in primary myometrium cells leads to transcriptional dysregulation of extracellular matrix associated genes and partly recapitulates transcriptional and epigenetic changes observed in leiomyomas. These findings establish AP-1 driven aberrant enhancer regulation as an important mechanism of leiomyoma disease pathogenesis.

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Section: Discussionsupporting

confidence: 91%

Altered chromatin landscape and enhancer engagement underlie transcriptional dysregulation in MED12 mutant uterine leiomyomas

2020

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“…4H ). Prior biochemical studies have shown that these mutations disrupt the ability of human MED12 to activate CDK8/CycC ( 19 , 20 , 42 ). Nonetheless, the molecular basis for these biochemical observations has remained obscure.…”

Section: Resultsmentioning

confidence: 99%

“…Our studies further clarify the molecular basis of MED12 in human disease. In this regard, numerous pathogenic alterations, including germline mutations causing the intellectual disability disorders FG, Lujan, and Ohdo syndromes, as well as somatic driver mutations leading to UL, breast fibroadenomas, and prostate cancer, have been found in human MED12 ( 31 – 35 , 42 , 54 , 55 ). In general, different types of disease mutations are mapped on different regions of Med12, indicating that disease type–specific mutations in MED12 may differentially affect its function (fig.…”

Section: Discussionmentioning

confidence: 99%

Structure and noncanonical Cdk8 activation mechanism within an Argonaute-containing Mediator kinase module

Chao

Kim

et al. 2021

Sci. Adv.

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The Cdk8 kinase module (CKM) in Mediator, comprising Med13, Med12, CycC, and Cdk8, regulates RNA polymerase II transcription through kinase-dependent and -independent functions. Numerous pathogenic mutations causative for neurodevelopmental disorders and cancer congregate in CKM subunits. However, the structure of the intact CKM and the mechanism by which Cdk8 is non-canonically activated and functionally affected by oncogenic CKM alterations are poorly understood. Here, we report a cryo–electron microscopy structure of Saccharomyces cerevisiae CKM that redefines prior CKM structural models and explains the mechanism of Med12-dependent Cdk8 activation. Med12 interacts extensively with CycC and activates Cdk8 by stabilizing its activation (T-)loop through conserved Med12 residues recurrently mutated in human tumors. Unexpectedly, Med13 has a characteristic Argonaute-like bi-lobal architecture. These findings not only provide a structural basis for understanding CKM function and pathological dysfunction, but also further impute a previously unknown regulatory mechanism of Mediator in transcriptional modulation through its Med13 Argonaute-like features.

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“…A recent study spanned CDK8-CCNC binding sites in MED12 and found them clustered in the region starting from 15th amino acid from the N-terminal region till 80th amino acid (Park et al, 2018a). It is to be noted that all mutations in MED12 in uterine leiomyomas are reported within this region.…”

Section: Activation Of Cyclin C-cdk8/19mentioning

confidence: 98%

Insights into the regulatory role and clinical relevance of mediator subunit, MED12, in human diseases

Srivastava

Kulshreshtha

2020

Journal Cellular Physiology

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Transcriptional dysregulation is central to many diseases including cancer. Mutation or deregulated expression of proteins involved in transcriptional machinery leads to aberrant gene expression that disturbs intricate cellular processes of division and differentiation. The subunits of the mediator complex are master regulators of stimuli‐derived transcription and are essential for transcription by RNA polymerase II. MED12 is a part of the CDK8 kinase module of the mediator complex and is essential for kinase assembly and function. Other than its function in activation of the kinase activity of CDK8 mediator, it also brings about transcription repression or activation, in response to several signalling pathways, a function that is independent of its role as a part of kinase assembly. Accumulating evidence suggests that MED12 controls complex transcription programs that are defining in cell fate determination, differentiation, and carcinogenesis. Mutations or differential expression of MED12 manifest in several human disorders and diseases. For instance, MED12 mutations are the gold standard for the diagnosis of several X‐linked intellectual disability syndromes. Further, certain MED12 mutations are categorised as driver mutations in carcinogenesis as well. This is a timely review that provides for the first time a wholesome view on the critical roles and pathways regulated by MED12, its interactions along with the implications of MED12 alterations/mutations in various cancers and nonneoplastic disorders. Based on the preclinical studies, MED12 indeed emerges as an attractive novel therapeutic target for various diseases and intellectual disorders.

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Mediator Kinase Disruption in MED12-Mutant Uterine Fibroids From Hispanic Women of South Texas

Cited by 25 publications

References 39 publications

Altered chromatin landscape and enhancer engagement underlie transcriptional dysregulation in MED12 mutant uterine leiomyomas

Altered chromatin landscape and enhancer engagement underlie transcriptional dysregulation in MED12 mutant uterine leiomyomas

Structure and noncanonical Cdk8 activation mechanism within an Argonaute-containing Mediator kinase module

Insights into the regulatory role and clinical relevance of mediator subunit, MED12, in human diseases

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