The co-existence of transcriptional activator and transcriptional repressor MEF2 complexes influences tumor aggressiveness

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.

Linking aberrant chromatin features in chronic lymphocytic leukemia to transcription factor networks

“…A bivalent signature switch at CLL promoters characterized by a loss of the active H3K4me3 mark points to a reduced developmental plasticity of CLL cells. According to our analysis, loss of H3K4me3 is predicted to occur via MEF2 TFs (Aziz et al , ; Di Giorgio et al , ) and reduced KMT2 activity. Furthermore, we find a number of additional links in our core TF network to modifiers of H3K4me3 that included, for example, KMT2E, KDM5A, SETD7 (Appendix Fig S7, Dataset EV14).…”

“…In ~ 1,700 CLL promoters that lost H3K4me3, binding motifs of the MEF2 family of transcriptional activators were enriched (Fig G). The MEF2 family TFs were suggested to regulate H3K4me3 (Pon & Marra, ; Di Giorgio et al , ) also in the context of H3K27me3 (Aziz et al , ). Furthermore, the H3K4‐specific methylases KMT2B (MLL2) and KMT2D (MLL4), and to a lesser degree also KMT2A/C/E, were downregulated in CLL (Fig EV3F).…”

Unscheduled HDAC4 repressive activity in human fibroblasts triggers TP53‐dependent senescence and favors cell transformation

“…pMXPIE‐Puro HDAC4‐WT/TM, H‐RAS/G12V were obtained by subcloning with a PCR method the ORF into the 4 hydroxy‐tamoxifen (4‐OHT)‐ inducible pMXPIE plasmid (Toledo et al ., ). The plasmids used to silence MEF2D and plasmids encoding for MEF2D‐FLAG and MEF2‐Engrailed FLAG (MEF2‐ENG) were previously described (Di Giorgio et al ., , ). For lentivirus‐based knock‐down, HEK‐293T cells were transfected with 1.8 μg of VSV‐G, 5 μg of Δ8.9 and 8 μg of pLKO plasmids.…”

“…After 36 h at 37°C, virions were collected and opportunely diluted in fresh medium. Retroviral infections were performed as previously described (Di Giorgio et al, 2017).…”

“…Immunofluorescence and immunoblotting were performed as previously described (Di Giorgio et al, 2017). Briefly, cells were fixed with 3% paraformaldehyde and permeabilized with 0.1% Triton X-100.…”