A5061300772- Epigenetics and DNA Methylation
- Genetics and Neurodevelopmental Disorders
- Genomics and Chromatin Dynamics
- RNA modifications and cancer
- RNA Research and Splicing
- Chromatin Remodeling and Cancer
- Autism Spectrum Disorder Research
- Histone Deacetylase Inhibitors Research
- Ubiquitin and proteasome pathways
- Neuroinflammation and Neurodegeneration Mechanisms
- Computational Drug Discovery Methods
- Neuroendocrine regulation and behavior
- Neuroscience and Neuropharmacology Research
- Cancer-related gene regulation
- Adipose Tissue and Metabolism
- MicroRNA in disease regulation
- Cancer-related molecular mechanisms research
- Genomic variations and chromosomal abnormalities
- Stress Responses and Cortisol
- Nuclear Receptors and Signaling
- Protein Degradation and Inhibitors
- Signaling Pathways in Disease
- DNA Repair Mechanisms
- Chromosomal and Genetic Variations
- Memory and Neural Mechanisms
University of Ottawa
2023-2025
University of Toronto
2018-2023
San Raffaele University of Rome
2016-2021
Hospital for Sick Children
2020
Istituti di Ricovero e Cura a Carattere Scientifico
2018
Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele
2018
Vita-Salute San Raffaele University
2012-2018
University of Milan
2017
University of Insubria
2014
Rett syndrome (RTT) is a neurodevelopmental disorder with no efficient treatment that caused in the majority of cases by mutations gene methyl-CpG binding-protein 2 (MECP2). RTT becomes manifest after period apparently normal development and causes growth deceleration, severe psychomotor impairment mental retardation. Effective animal models for are available show morphofunctional abnormalities synaptic connectivity. However, molecular consequences MeCP2 disruption leading to neuronal...
Histone variants were recently discovered to regulate neural plasticity, with H2A.Z emerging as a memory suppressor. Using whole-genome sequencing of the mouse hippocampus, we show that basal occupancy is positively associated steady-state transcription, whereas learning-induced removal gene expression. AAV-mediated depletion enhanced fear and resulted in gene-specific alterations reinforcing role accumulated age, although it remained sensitive eviction. Learning-related occurred at largely...
Abstract Creating long-lasting memories requires learning-induced changes in gene expression, which are impacted by epigenetic modifications of DNA and associated histone proteins. Post-translational (PTMs) histones key regulators transcription, with different PTMs producing unique effects on activity behavior. Although recent studies implicate variants as novel memory, the function rarely considered. We previously showed that variant H2A.Z suppresses but it is unclear if this role...
The chromatin remodeler SRCAP plays a critical role in depositing the histone variant H2A.Z, which is essential for transcriptional regulation, accessibility, and neurodevelopmental processes. Despite its known importance, mechanisms by regulates H2A.Z dynamics during neuronal differentiation remain poorly understood. Here, we investigated impact of Srcap knockdown on incorporation regulation N2A cells. Chromatin immunoprecipitation (ChIP) revealed reduced occupancy at activity-dependent...
Memory formation is a protracted process that initially involves the hippocampus and becomes increasingly dependent on cortex over time, but mechanisms of this transfer are unclear. We recently showed hippocampal depletion histone variant H2A.Z enhances both recent remote memories, use virally mediated reduced levels throughout testing, making its temporally specific function Given lack drugs target variants, we tested existing for efficacy against based their targeting known regulators. The...
Abstract Emerging evidence suggests that histone variants are novel epigenetic regulators of memory, whereby H2A.Z suppresses fear memory. However, it is not clear if altered memory can also modify risk for PTSD, and whether these effects differ in males females. Using conditional-inducible knockout (cKO) mice, we showed binding higher females cKO enhanced only males. improved on the non-aversive object-in-place task both sexes, suggesting non-stressful irrespective sex. Given fear-related...
Mutations in MECP2 cause a broad spectrum of neuropsychiatric disorders which Rett syndrome represents the best defined condition. Both neuronal and non-neuronal functions methyl-binding protein underlie related pathologies. Nowadays MeCP2 is recognized as multifunctional that modulates its activity depending on partners posttranslational modifications. However, we are still missing comprehensive understanding all their involvement The study human mutations often offers possibility...
Abstract MeCP2 is a transcriptional regulator whose functional alterations are responsible for several autism spectrum and mental disorders. Post-translational modifications (PTMs) particularly differential phosphorylation, modulate function in response to diverse stimuli. Understanding the detailed role of phosphorylation thus instrumental ascertain how integrates environmental signals directs its adaptive responses. The evolutionarily conserved serine 164 (S164) was found phosphorylated...
Rapid removal of histone H2A.Z from neuronal chromatin is a key step in learning-induced gene expression and memory formation, but mechanisms underlying are unclear. Anp32e was recently identified as an H2A.Z-specific chaperone that removes nucleosomes dividing cells, its role non-dividing neurons Moreover, prior studies investigated function under steady-state rather than stimulus-induced conditions. Here, we show regulates binding conditions, with lesser impact on removal. Functionally,...
Abstract Histone variants H2A.Z and H3.3 are epigenetic regulators of memory, but roles other not well characterized. macroH2A (mH2A) is a structurally unique histone that contains globular macrodomain connected to the region by an unstructured linker. Here we assessed if mH2A regulates memory this role varies for two mH2A-encoding genes, H2afy (mH2A1) H2afy2 (mH2A2). We show fear impaired in mH2A1, mH2A2-deficient mice, whereas both groups were non-aversive spatial task. However, impairment...
The replication independent (RI) histone H2A.Z is one of the more extensively studied variant members core H2A family, which consists many dependent (RD) members. protein has been shown to be indispensable for survival, and involved in multiple roles from DNA damage chromosome segregation, replication, transcription. However, its functional involvement gene expression controversial. Moreover, several groups metazoan organisms two main isoforms (H2A.Z-1 H2A.Z-2) that differ a few (3–6) amino...
MeCP2 binds to methylated DNA in a chromatin context and has an important role cancer brain development function. Histone deacetylase (HDAC) inhibitors are currently being used palliate many neurological disorders. Yet, the molecular mechanisms involved not well known for most part and, particular, relationship between histone acetylation is understood. In this paper, we study effect of HDAC inhibitor trichostatin A (TSA) on MeCP2, protein whose dysregulation plays these diseases. We find...
Abstract Background There is growing evidence that dysregulation of gene expression plays a role in cognitive deficits and neuropathology Alzheimer’s disease (AD), thus prompting interest epigenetic factors as mechanisms neurodegeneration memory loss. Here, we assess the therapeutic potential histone variant H2A.Z. H2A.Z suppressor actively removed from DNA during learning to promote formation. The memory‐suppressive effects are further supported by our finding levels increase aged brain may...
An amendment to this paper has been published and can be accessed via a link at the top of paper.