MEF2s are pleiotropic transcription factors (TFs) which supervise multiple cellular activities. During the cell cycle, MEF2s are activated at the G 0 /G 1 transition to orchestrate the expression of the immediate early genes in response to growth factor stimulation. Here we show that, in human and murine fibroblasts, MEF2 activities are downregulated during late G 1 . MEF2C and MEF2D interact with the E3 ligase F-box protein SKP2, which mediates their subsequent degradation through the ubiquitinproteasome system. The cyclin-dependent kinase 4 (CDK4)/cyclin D1 complex phosphorylates MEF2D on serine residues 98 and 110, and phosphorylation of these residues is an important determinant for SKP2 binding. Unscheduled MEF2 transcription during the cell cycle reduces cell proliferation, whereas its containment sustains DNA replication. The CDK inhibitor p21/ CDKN1A gene is a MEF2 target gene required to exert this antiproliferative influence. MEF2C and MEF2D bind a region within the first intron of CDKN1A, presenting epigenetic markers of open chromatin. Importantly, H3K27 acetylation within this regulative region depends on the presence of MEF2D. We propose that following the initial engagement in the G 0 /G 1 transition, MEF2C and MEF2D must be polyubiquitylated and degraded during G 1 progression to diminish the transcription of the CDKN1A gene, thus favoring entry into S phase. In vertebrates, the family of MEF2s comprises 4 members-MEF2A, -B, -C, and -D-as well as some splicing variants (1). Common features of all MEF2 members are the MADS box (MCM1, agamous, deficiens, serum response factor) and the adjacent MEF2 domain positioned within the highly conserved amino-terminal region (1). These domains are involved in recognizing the YTA(A/T) 4 TAR DNA motif, in mediating the formation of homo-and heterodimers, and in the interaction with different cofactors (1). The carboxy-terminal half is much less conserved. It encompasses the transactivation domains and the nuclear localization signal (2). The different family members exhibit specific but also overlapping patterns of expression, during either embryogenesis or adult life (1, 3). MEF2s are subjected to intense supervision by environmental signals, in order to couple the gene expression signature to the organism requirements (1). MEF2s oversee the expression of several genes, depending on and in cooperation with other transcription factors (TFs) (3, 4). In addition, MEF2s can also operate as repressors of transcription when in complexes with class IIa histone deacetylases (HDACs) (5,6,7,8).The extent of genes under the influence of MEF2s justifies the pleiotropic activities and the assorted cellular responses attributed to these TFs. During development, in general, expression of MEF2 is linked to the activation of differentiation programs (1). In various scenarios, the onset of MEF2 expression coincides with the withdrawal from the cell cycle (9). Specific ablation of MEF2C in neural/progenitor cells impacts differentiation but not their survival or proliferation (...

The prospect of intervening, through the use of a specific molecule, with a cellular alteration responsible for a disease, is a fundamental ambition of biomedical science. Epigenetic-based therapies appear as a remarkable opportunity to impact on several disorders, including cancer. Many efforts have been made to develop small molecules acting as inhibitors of histone deacetylases (HDACs). These enzymes are key targets to reset altered genetic programs and thus to restore normal cellular activities, including drug responsiveness. Several classes of HDAC inhibitors (HDACis) have been generated, characterized and, in certain cases, approved for the use in clinic. A new frontier is the generation of subtype-specific inhibitors, to increase selectivity and to manage general toxicity. Here we will discuss about a set of molecules, which can interfere with the activity of a specific subclass of HDACs: the class IIa.

Scrapie resistance or susceptibility in sheep is associated with single nucleotide polymorphisms (SNPs) at codons 136, 154, and 171 of the prion protein gene ( PRNP). In addition, phenylalanine mutation at codon 141 has been recognized as a risk factor for atypical scrapie. In contrast, K222, D146, and S146 alleles confer genetic resistance to classical scrapie in goats. High-throughput genotyping technologies would provide significant benefits in scrapie eradication plans. The ability to resolve oligonucleotides varying in mass by less than a single nucleotide makes MALDI-TOF mass spectrometry (MS) a suitable platform for PRNP genotyping. We evaluated the commercial Myriapod scrapie kit (Diatech Pharmacogenetics), associated with a highly automated processing platform incorporating MALDI-TOF MS technology, to detect SNPs at codons 136, 154, 171, 141, and 222 of small ruminant PRNP. The Myriapod scrapie kit was accredited according to UNI CEI EN ISO/IEC 17025. We present the genotyping results of 10,960 sheep in Sicily and 1,822 goats in Sicily and Calabria (southern Italy) tested during 2017. We found a high frequency (43.9%) of the protective ARR allele in sheep and a promising 12.3% of the resistant K222 variant in goats. This efficient and high-throughput method is suitable for extensive PRNP genotyping, as requested in the European scrapie eradication plan.