You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.

Title: The co-existence of transcriptional activator and transcriptional repressor MEF2 complexes influences tumor aggressiveness}
Article:
Abstract:
The contribution of MEF2 TFs to the tumorigenic process is still mysterious. Here we clarify that MEF2 can support both pro-oncogenic or tumor suppressive activities depending on the interaction with co-activators or co-repressors partners. Through these interactions MEF2 supervise histone modifications associated with gene activation/repression, such as H3K4 methylation and H3K27 acetylation. Critical switches for the generation of a MEF2 repressive environment are class IIa HDACs. In leiomyosarcomas( LMS), this two-faced trait of MEF2 is relevant for tumor aggressiveness. Class IIa HDACs are overexpressed in 22% of LMS, where high levels of MEF2, HDAC4 and HDAC9 inversely correlate with overall survival. The knock out of HDAC9 suppresses the transformed phenotype of LMS cells, by restoring the transcriptional proficiency of some MEF2-target loci. HDAC9 coordinates also the demethylation of H3K4me3 at the promoters of MEF2-target genes. Moreover, we show that class IIa HDACs do not bind all the regulative elements bound by MEF2. Hence, in a cell MEF2-target genes actively transcribed and strongly repressed can coexist. However, these repressed MEF2-targets are poised in terms of chromatin signature. Overall our results candidate class IIa HDACs and HDAC9 in particular, as druggable targets for a therapeutic intervention in LMS.
Introduction:
MEF2 is a family of transcriptional regulators involved in the control of pleiotropic responses during development and adult life. In vertebrates four members, MEF2A/B/C/D, compose the family. MEF2 are characterized by the presence of a highly conserved N-terminal MADS/MEF2 domain involved in dimerization and DNA-binding, followed by the less conserved C-terminal transactivation region[1]. Although some actions of MEF2 are redundant, functional studies have also credited specific activities to each member of the family[2–6]. The transcriptional programs under MEF2 supervision diverge in different cell types. MEF2-targets include genes involved in various differentiation activities[7–9]. Some of these targets must be switched off, if they are not part of the ongoing differentiation program, even though a transcriptionally active MEF2 is present in the same cell. Dominant epigenetic regulations and/or the existence of multiple MEF2 transcriptional partners contribute to orchestrate the context-dependent MEF2 transcriptional landscape[3, 4, 8]. The four family members and their splicing variants can provide further layers of complexity to the MEF2 transcriptome[10–13]. Furthermore, MEF2 can be converted into transcriptional repressors after the binding to Cabin1, G9a or class IIa HDACs[14–16]. Among these transcriptional co-repressors, class IIa HDACs( HDAC4/5/7/9) play a pivotal role and their activity is subjected to tight cellular and environmental controls[17]. Dysfunctions in MEF2 characterize several pathological conditions, including cognitive disorders, cardiac hypertrophy and cancer[18–21]. Specifically, pro-oncogenic roles of MEF2 have been reported for certain hematological malignancies and hepatocarcinomas, which are linked to the increased expression, mutations or genetic rearrangements of these TFs[22–27]. By contrast, actions as tumor suppressors have been described in the case of soft-tissue sarcomas or in the case of mutations, mostly of MEF2B, in non-Hodgking lymphomas[11, 28–30]. The antagonistic roles of MEF2 in oncogenesis, suggested by these studies, cannot be completely explained by the context-dependent regulation of their target genes[24, 30–32]. In this scenario, the ability of MEF2 to act either as transcriptional activators or as repressors on varying the environmental and genetic backgrounds has been so far underestimated. Hence, we decided to address this point by dissecting the contribution of MEF2 to the tumorigenic process using the leiomyosarcomas( LMS) as a model. LMS are rare soft tissue sarcomas showing certain degrees of smooth muscle differentiation[33, 34]. In this manuscript we have explored the transcriptional landscape and the epigenetic modifications under the control of these TFs in relation to the tumorigenic process.
Discussion:
The involvement of MEF2 in the tumorigenic process is still enigmatic[21–30, 41]. In this manuscript we provide evidences that could help to solve this controversial issue. We took advantage from the leiomyosarcoma model to unveil the two-faced of MEF2, but we are confident that these results can be confirmed also in other cancer types. Our studies suggest that LMS can be clustered in two groups, in terms of MEF2 dysfunctions. The first group exhibited low proliferation and low levels of MEF2 proteins, possibly because of the SKP2-mediated degradation[35, 42]. The second group comprised tumors with high expression of MEF2 and of class IIa HDACs. Under these conditions MEF2 are converted into transcriptional repressors. The combination of high MEF2 and class IIa HDACs levels is detrimental for patients’ survival. Although the UPS-mediated degradation can remove MEF2 from promoters and enhancers, their conversion into repressors can provide a strongest silencing, which is translated in a worse prognosis. HDAC4, HDAC5 and HDAC9 or its splicing variant MITR are the class IIa HDACs more frequently overexpressed in LMS. A condition not limited to this tumor type, as testified by recent studies[43–47]. These observations can be recapitulated in two LMS cell lines. In SK-LMS-1 cells MEF2 are under UPS control. MEF2 ablation reduces the expression of MEF2-target genes and enhances the transformed phenotype. By contrast in SK-UT-1 cells, where HDAC9 is highly expressed, MEF2 are required for tumorigenesis and to repress the transcription of some MEF2-target genes. This conversion stems from MEF2 assembly into multi-protein repressive complexes, which erase histone marks of open chromatin configuration, such as H3K4me3 and H3K27ac, and thus repress the transcription of some MEF2-target genes( Fig 9F). Our genes expression profile studies confirmed the complexity of the MEF2-trascriptome[2, 8, 48, 49]. Common as well as cell type and isoform specific MEF2-regulated genes exist. This multifaceted scenario could result from: i) a certain degree in DNA binding preferences of the different MEF2[50]; ii) the presence of specific PTMs[1] and iii) the ability of forming complexes with other TFs, which hijack MEF2 away from canonical targets[4, 8]. Beside this complexity, we identified a common MEF2 signature, which can explain the opposite impact of MEF2 in the two LMS cells. Regulators of EMT, of the cell cycle and of inflammation are significantly enriched in this signature. Several genes of this signature are repressed by MEF2 in SK-UT-1 cells. HDAC9 is the key factor for switching MEF2 into a repressor. However, HDAC9 is not recruited onto all promoters bound by MEF2. Hence, some MEF2-target genes are not repressed, even though SK-UT-1 cells express high levels of HDAC9. It is possible that these MEF2-targets govern some crucial activities of cancer cells. The coexistence in the same cell population of TFs with both suppressive and activating activities on different loci, although surprising, was previously observed[48, 51, 52]. Different hypothesis have been formulated to explain this paradox but without a conclusive demonstration. We can exclude that the distance of the MEF2 binding site from the TSS could play a role, as previously hypothesized[48]. Since the repressive switch is cell lineage-dependent rather than gene-dependent, we could also exclude contributions of differences in the consensus of binding between promoters, as observed for p53[52]. A fascinating hypothesis concerns contributions of the local nuclear organization, which might generate microenvironments proficient or exploitive for HDAC9 binding to MEF2. MEF2 are required for H3K27 acetylation and H3K4 methylation. These activities can be explained by their ability to interact with Ash2L, a core subunit of KMT2 methyltransferase[53] and with the acetyl-transferase p300/CBP[54]. MEF2, once in complex with HDAC9, govern H3K27 deacetylation and H3K4 demethylation. Class IIa HDACs can bind the complex HDAC3/NuRD/SMRT, which delivers the deacetylase activity. Currently, we do not know whether a H3K4 demethylase is part of the same repressive complex with HDAC9. In principle, HDAC9 could act as a scaffold for a DMTase, as previously reported for HDAC4 and HDAC5[55–57]. Interestingly, in SK-UT-1 cells genes repressed by MEF2-HDAC9 conserve H3K27 acetylation levels comparable to SK-LMS-1. These genes are in equilibrium between a closed and open chromatin conformation, similarly to the poised developmental regulatory genes in stem cells[58]. This condition would make possible to revert the transcriptional output of these genes by simply inhibiting the demethylase involved. Therapeutic intervention in advanced leiomyosarcomas represents a challenge. Important obstacles are the extreme genetic heterogeneity and the relatively low incidence of these malignancies[33, 34, 59]. Here we have found that over 20% of leiomyosarcomas present increased expression of a class IIa HDAC member. In vitro experiments indicate that the manipulation of the MEF2-HDAC axis impinges on the transformed phenotype. In conclusion, our discoveries suggest that small molecules targeting class IIa HDACs or the interaction between the deacetylase and MEF2 could afford success for the treatment of certain LMS.
The tumorigenic process is characterized by profound alterations of the transcriptional landscape , aimed to sustain uncontrolled cell growth , resistance to apoptosis and metastasis . The contribution of MEF2 , a pleiotropic family of transcription factors , to these changes is controversial , since both pro-oncogenic and tumor-suppressive activities have been reported . To clarify this paradox , we studied the role of MEF2 in an aggressive type of soft-tissue sarcomas , the leiomyosarcomas ( LMS ) . We found that in LMS cells MEF2 become oncogenes when in complex with class IIa HDACs . We have identified different sub-classes of MEF2-target genes and observed that HDAC9 converts MEF2 into transcriptional repressors on some , but not all , MEF2-regulated loci . This conversion correlates with the acquisition by MEF2 of oncogenic properties . We have also elucidated some epigenetic re-arrangements supervised by MEF2 . In summary , our studies suggest that the paradoxical actions of MEF2 in cancer can be explained by their dual role as activators/repressors of transcription and open new possibilities for therapeutic interventions .