Progesterone receptor integrates the effects of mutated MED12 and altered DNA methylation to stimulate RANKL expression and stem cell proliferation in uterine leiomyoma

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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“…was also found to drive expression from progesterone responsive promoters in uterine leiomyomas (Liu et al, 2019).…”

Section: Oestrogen and Progesterone Signallingmentioning

confidence: 94%

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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“…Complementary deoxyribonucleic acid was synthesized using qScript cDNA SuperMix (total RNA >100 ng; 95048–100, VWR International, Radnor, Pennsylvania) or SuperScript VILO Master Mix (total RNA <100 ng; 11754050, Thermo Fisher Scientific, Waltham, Massachusetts). Messenger RNA (mRNA) levels were quantified using real-time quantitative polymerase chain reaction (qPCR) normalized to TATA-BOX Binding Protein (TBP), as previously described ( 21 ). Total RNA quality was examined using the Bioanalyzer RNA Pico assay (Agilent, Santa Clara, California).…”

Section: Methodsmentioning

confidence: 99%

Targeting DNA Methylation Depletes Uterine Leiomyoma Stem Cell–enriched Population by Stimulating Their Differentiation

Liu

Yin

et al. 2020

Endocrinology

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Uterine leiomyoma is the most common tumor in women and can cause severe morbidity. Leiomyoma growth requires maintenance and proliferation of a stem cell population. Dysregulated DNA methylation has been reported in leiomyoma, but its role in leiomyoma stem cell regulation remains unclear. Here, we FACS sorted cells from human leiomyoma tissues into three populations: stem-cell like cells (LSC, 5%), intermediate cells (LIC, 7%), and differentiated cells (LDC, 88%) and analyzed the transcriptome and epigenetic landscape of leiomyoma cells at different differentiation stages. LSC harbored a unique methylome, with 8862 differentially methylated regions compared to LIC and 9444 compared to LDC, most of which were hypermethylated. Consistent with global hypermethylation, transcript levels of TET1 and TET3 methylcytosine dioxygenases were lower in LSC. Integrative analyses revealed an inverse relationship between methylation and gene expression changes during LSC differentiation. In LSC, hypermethylation suppressed genes important for myometrium- and leiomyoma-associated functions, including muscle contraction and hormone action, to maintain stemness. The hypomethylating drug, 5'-Aza stimulated LSC differentiation, depleting the stem cell population and inhibiting tumor initiation. Our data suggest that DNA methylation maintains the pool of LSC, which is critical for the regeneration of leiomyoma tumors.

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“…Numerous data have been obtained that indicate global disorders in methylation/demethylation of the genome in LM cells [49][50][51]. This indicates an important contribution of epigenetic regulation disorders to the pathogenesis of this disease [43,52].…”

Section: Epigenetic Regulationmentioning

confidence: 97%

“…It has been established that microRNAs are the regulators of LM growth, and, first of all, miR-15b, which increases the expression of genes that control cell proliferation and affects the receptivity of estrogen and progesterone [50].…”

Section: General Considerationsmentioning

confidence: 99%

Pathogenomics of Uterine Fibroids Development

Baranov

Osinovskaya

Yarmolinskaya

2019

IJMS

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We review recent studies dealing with the molecular genetics and basic results of omics analysis of uterine leiomyoma (LM)—a common benign muscle tumor of the uterus. Whole genome studies of LM resulted in the discovery of many new gene nets and biological pathways, including its origin, transcriptomic, and epigenetic profiles, as well as the impact of the inter-cell matrix in LM growth and involvement of microRNA in its regulation. New data on somatic cell mutations ultimately involved in the origin, distribution and growth of LM are reviewed. Putative identification of LM progenitor SC (stem cells) giving rise to maternal fibroid nodes and junctional zones provide a new clue for hypotheses on the pathogenomics of LM. The reviewed data are consistent with at least two different but probably intimately interacted molecular mechanisms of LM. One of them (the genetic hypothesis) is focused primarily on the MED12 gene mutations and suggests its onset in the side population of embryonic myoblasts of the female reproductive system, which later gave rise to multiple small and medium fibroids. The single and usually large-size fibroids are induced by predominantly epigenetic disorders in LM SC, provoked by enhanced expression of the HMGA2 gene caused by its hypomethylation and epigenetic deregulation enhanced by hypoxia, muscle tension, or chromosome instability/aberrations. The pathogenomics of both genetic and epigenetic programs of LM with many peculiarities at the beginning later became rather similar and partly overlapped due to the proximity of their gene nets and epigenetic landscape. Pathogenomic studies of LM open ways for elaboration of novel strategies of prevention and treatment of this common disease.

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Progesterone receptor integrates the effects of mutated MED12 and altered DNA methylation to stimulate RANKL expression and stem cell proliferation in uterine leiomyoma

Cited by 40 publications

References 50 publications

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

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

Targeting DNA Methylation Depletes Uterine Leiomyoma Stem Cell–enriched Population by Stimulating Their Differentiation

Pathogenomics of Uterine Fibroids Development

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