Ricerc@Sapienza

Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. HVDAS is caused by mutations in activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with HVDAS, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with HVDAS into two groups based on the location of the mutations.

The 'instructive model' of aberrant DNA methylation in human tumors is based on the observation that CpG islands prone to hypermethylation in cancers are embedded in chromatin enriched in H3K27me3 in human embryonic stem cells (hESC). Recent studies also link methylation of CpG islands to the methylation status of H3K4, where H3K4me3 is inversely correlated with DNA methylation.

Medulloblastoma (MB) is the most common malignant brain tumor in children and among the subtypes, Group 3 MB has the worst outcome. Here, we perform an in vivo, patient-specific screen leading to the identification of Otx2 and c-MYC as strong Group 3 MB inducers. We validated our findings in human cerebellar organoids where Otx2/c-MYC give rise to MB-like organoids harboring a DNA methylation signature that clusters with human Group 3 tumors.

The functional role of cytosine methylation in the CpG moieties of DNA, is well established in several biological functions. The interplay between CpG methylation and hypomethylation is a well-known mechanism of modulation of gene expression. However, the role of non-CpG methylation and active dynamics of demethylation is not clearly recognized. Although some evidence exists of a role of active non-CpG demethylation in the fast dynamics of transcriptional activation in animals, few studies deal with this topic.

PURPOSE OF REVIEW: Unraveling the diet-epigenetics-neurodegeneration connection may disclose associated mechanisms and novel approaches to the neurodegenerative diseases. This review summarizes the basic concepts and the innovative results in this field focusing on the relevance of non-CpG methylation. RECENT FINDINGS: Many multifactorial neurodegenerative diseases are associated with epigenetic changes, and the brain seems more prone to epigenetic changes than other tissues.

Epigenetics regulate gene function without any alteration in the DNA sequence. The epigenetics represent one of the most important regulators in different cellular processes and have initially been developed in microorganisms as a protective strategy. The evaluation of the epigenetic mechanisms is also important in achieving an efficient control strategy in tuberculosis (TB). TB is one of the most significant epidemiological concerns in human history.

The short, non-coding RNAs, also called microRNAs (miRNAs) can bind complementary sequences on cellular mRNAs. The consequence of this binding is generally the degradation of mRNA and the inhibition of its translation. For this reason, miRNAs are included among the epigenetic factors acting as a modulator of gene expression. How miRNAs expression is, in turn, regulated is still the object of active investigation, but DNA methylation, another epigenetic modification, seems to play a central role in this sense.