Functional Connectivity States of Alpha Rhythm Sources in the Human Cortex at Rest: Implications for Real-Time Brain State Dependent EEG-TMS.

Alpha is the predominant rhythm of the human electroencephalogram, but its function, multiple generators and functional coupling patterns are still relatively unknown. In this regard, alpha connectivity patterns can change between different cortical generators depending on the status of the brain. Therefore, in the light of the communication through coherence framework, an alpha functional network depends on the functional coupling patterns in a determined state. This notion has a relevance for brain-state dependent EEG-TMS because, beyond the local state, a network connectivity overview at rest could provide further and more comprehensive information for the definition of 'instantaneous state' at the stimulation moment, rather than just the local state around the stimulation site. For this reason, we studied functional coupling at rest in 203 healthy subjects with MEG data. Sensor signals were source localized and connectivity was studied at the Individual Alpha Frequency (IAF) between three different cortical areas (occipital, parietal and prefrontal). Two different and complementary phase-coherence metrices were used. Our results show a consistent connectivity between parietal and prefrontal regions whereas occipito-prefrontal connectivity is less marked and occipito-parietal connectivity is extremely low, despite physical closeness. We consider our results a relevant add-on for informed, individualized real-time brain state dependent stimulation, with possible contributions to novel, personalized non-invasive therapeutic approaches.

A New Framework to Interpret Individual Inter-Hemispheric Compensatory Communication after Stroke.

Stroke constitutes the main cause of adult disability worldwide. Even after application of standard rehabilitation protocols, the majority of patients still show relevant motor impairment. Outcomes of standard rehabilitation protocols have led to mixed results, suggesting that relevant factors for brain re-organization after stroke have not been considered in explanatory models. Therefore, finding a comprehensive model to optimally define patient-dependent rehabilitation protocols represents a crucial topic in clinical neuroscience. In this context, we first report on the rehabilitation models conceived thus far in the attempt of predicting stroke rehabilitation outcomes. Then, we propose a new framework to interpret results in stroke literature in the light of the latest evidence regarding: (1) the role of the callosum in inter-hemispheric communication, (2) the role of prefrontal cortices in exerting a control function, and (3) diaschisis mechanisms. These new pieces of evidence on the role of callosum can help to understand which compensatory mechanism may take place following a stroke. Moreover, depending on the individual impairment, the prefrontal control network will play different roles according to the need of high-level motor control. We believe that our new model, which includes crucial overlooked factors, will enable clinicians to better define individualized motor rehabilitation protocols.

MeCP2 and Major Satellite Forward RNA Cooperate for Pericentric Heterochromatin Organization.

Methyl-CpG binding protein 2 (MeCP2) has historically been linked to heterochromatin organization, and in mouse cells it accumulates at pericentric heterochromatin (PCH), closely following major satellite (MajSat) DNA distribution. However, little is known about the specific function of MeCP2 in these regions. We describe the first evidence of a role in neurons for MeCP2 and MajSat forward (MajSat-fw) RNA in reciprocal targeting to PCH through their physical interaction. Moreover, MeCP2 contributes to maintenance of PCH by promoting deposition of H3K9me3 and H4K20me3. We highlight that the MeCP2B isoform is required for correct higher-order PCH organization, and underline involvement of the methyl-binding and transcriptional repression domains. The T158 residue, which is commonly mutated in Rett patients, is directly involved in this process. Our findings support the hypothesis that MeCP2 and the MajSat-fw transcript are mutually dependent for PCH organization, and contribute to clarify MeCP2 function in the regulation of chromatin architecture.

Author Correction: Cortical source localization of sleep-stage specific oscillatory activity.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Interpretation of the Epigenetic Signature of Facioscapulohumeral Muscular Dystrophy in Light of Genotype-Phenotype Studies.

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by incomplete penetrance and intra-familial clinical variability. The disease has been associated with the genetic and epigenetic features of the D4Z4 repetitive elements at 4q35. Recently, D4Z4 hypomethylation has been proposed as a reliable marker in the FSHD diagnosis. We exploited the Italian Registry for FSHD, in which FSHD families are classified using the Clinical Comprehensive Evaluation Form (CCEF). A total of 122 index cases showing a classical FSHD phenotype (CCEF, category A) and 110 relatives were selected to test with the receiver operating characteristic (ROC) curve, the diagnostic and predictive value of D4Z4 methylation. Moreover, we performed DNA methylation analysis in selected large families with reduced penetrance characterized by the co-presence of subjects carriers of one D4Z4 reduced allele with no signs of disease or presenting the classic FSHD clinical phenotype. We observed a wide variability in the D4Z4 methylation levels among index cases revealing no association with clinical manifestation or disease severity. By extending the analysis to family members, we revealed the low predictive value of D4Z4 methylation in detecting the affected condition. In view of the variability in D4Z4 methylation profiles observed in our large cohort, we conclude that D4Z4 methylation does not mirror the clinical expression of FSHD. We recommend that measurement of this epigenetic mark must be interpreted with caution in clinical practice.

Cortical source localization of sleep-stage specific oscillatory activity.

The oscillatory features of non-REM sleep states have been a subject of intense research over many decades. However, a systematic spatial characterization of the spectral features of cortical activity in each sleep state is not available yet. Here, we used magnetoencephalography (MEG) and electroencephalography (EEG) recordings during night sleep. We performed source reconstruction based on the individual subject's anatomical magnetic resonance imaging (MRI) scans and spectral analysis on each non-REM sleep epoch in eight standard frequency bands, spanning the complete spectrum, and computed cortical source reconstructions of the spectral contrasts between each sleep state in comparison to the resting wakefulness. Despite not distinguishing periods of high and low activity within each sleep stage, our results provide new information about relative overall spectral changes in the non-REM sleep stages.

Praja1 E3 ubiquitin ligase promotes skeletal myogenesis through degradation of EZH2 upon p38α activation.

Polycomb proteins are critical chromatin modifiers that regulate stem cell differentiation via transcriptional repression. In skeletal muscle progenitors Enhancer of zeste homologue 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), contributes to maintain the chromatin of muscle genes in a repressive conformation, whereas its down-regulation allows the progression through the myogenic programme. Here, we show that p38α kinase promotes EZH2 degradation in differentiating muscle cells through phosphorylation of threonine 372. Biochemical and genetic evidence demonstrates that the MYOD-induced E3 ubiquitin ligase Praja1 (PJA1) is involved in regulating EZH2 levels upon p38α activation. EZH2 premature degradation in proliferating myoblasts is prevented by low levels of PJA1, its cytoplasmic localization and the lower activity towards unphosphorylated EZH2. Our results indicate that signal-dependent degradation of EZH2 is a prerequisite for satellite cells differentiation and identify PJA1 as a new player in the epigenetic control of muscle gene expression.

Polycomb dysregulation in gliomagenesis targets a Zfp423-dependent differentiation network.

Malignant gliomas constitute one of the most significant areas of unmet medical need, owing to the invariable failure of surgical eradication and their marked molecular heterogeneity. Accumulating evidence has revealed a critical contribution by the Polycomb axis of epigenetic repression. However, a coherent understanding of the regulatory networks affected by Polycomb during gliomagenesis is still lacking. Here we integrate transcriptomic and epigenomic analyses to define Polycomb-dependent networks that promote gliomagenesis, validating them both in two independent mouse models and in a large cohort of human samples. We find that Polycomb dysregulation in gliomagenesis affects transcriptional networks associated with invasiveness and de-differentiation. The dissection of these networks uncovers Zfp423 as a critical Polycomb-dependent transcription factor whose silencing negatively impacts survival. The anti-gliomagenic activity of Zfp423 requires interaction with the SMAD proteins within the BMP signalling pathway, pointing to a novel synergic circuit through which Polycomb inhibits BMP signalling.

Chromatin signaling in muscle stem cells: interpreting the regenerative microenvironment.

Muscle regeneration in the adult occurs in response to damage at expenses of a population of adult stem cells, the satellite cells. Upon injury, either physical or genetic, signals released within the satellite cell niche lead to the commitment, expansion and differentiation of the pool of muscle progenitors to repair damaged muscle. To achieve this goal satellite cells undergo a dramatic transcriptional reprogramming to coordinately activate and repress specific subset of genes. Although the epigenetics of muscle regeneration has been extensively discussed, less emphasis has been put on how extra-cellular cues are translated into the specific chromatin reorganization necessary for progression through the myogenic program. In this review we will focus on how satellite cells sense the regenerative microenvironment in physiological and pathological circumstances, paying particular attention to the mechanism through which the external stimuli are transduced to the nucleus to modulate chromatin structure and gene expression. We will discuss the pathways involved and how alterations in this chromatin signaling may contribute to satellite cells dysfunction during aging and disease.