DNA methylation and methyl-CpG binding proteins: developmental requirements and function

DNA methylation is a major epigenetic modification in the genomes of higher eukaryotes. In vertebrates, DNA methylation occurs predominantly on the CpG dinucleotide, and approximately 60% to 90% of these dinucleotides are modified. Distinct DNA methylation patterns, which can vary between different tissues and developmental stages, exist on specific loci. Sites of DNA methylation are occupied by various proteins, including methyl-CpG binding domain (MBD) proteins which recruit the enzymatic machinery to establish silent chromatin. Mutations in the MBD family member MeCP2 are the cause of Rett syndrome, a severe neurodevelopmental disorder, whereas other MBDs are known to bind sites of hypermethylation in human cancer cell lines. Here, we review the advances in our understanding of the function of DNA methylation, DNA methyltransferases, and methyl-CpG binding proteins in vertebrate embryonic development. MBDs function in transcriptional repression and long-range interactions in chromatin and also appear to play a role in genomic stability, neural signaling, and transcriptional activation. DNA methylation makes an essential and versatile epigenetic contribution to genome integrity and function

Measuring Implicit and Explicit Acceptability of Reinforcement Versus Punishment Interventions with Teachers Working in ABA Versus Mainstream Schools

This research aimed to develop the implicit relational assessment procedure (IRAP) as a measure of treatment acceptability and to assess teachers’ acceptability of reinforcement and punishment interventions in the presence of “good” and “bad” behaviors. Participants included 15 teachers trained in ABA (ABATs) who worked with children with developmental disabilities, and 15 teachers trained in mainstream primary education (MTs) who worked with typically developing children. On the IRAP, the ABAT group showed proreinforcement biases for all behaviors, while MTs showed a proreinforcement bias for good behavior but a propunishment bias for bad behavior. On explicit measures of acceptability, although both groups showed proreinforcement and antipunishment biases, the ABATs rated reinforcement as significantly more acceptable than the MTs; the ratings of punishment did not differ across the two groups. The research provides support for the IRAP as a measure of treatment acceptability

Novel variants identified in methyl-CpG-binding domain genes in autistic individuals

Misregulation of the methyl-CpG-binding protein 2 (MECP2) gene has been found to cause a myriad of neurological disorders including autism, mental retardation, seizures, learning disabilities, and Rett syndrome. We hypothesized that mutations in other members of the methyl-CpG-binding domain (MBD) family may also cause autistic features in individuals. We evaluated 226 autistic individuals for alterations in the four genes most homologous to MECP2: MBD1, MBD2, MBD3, and MBD4. A total of 46 alterations were identified in the four genes, including ten missense changes and two deletions that alter coding sequence. Several are either unique to our autistic population or cosegregate with affected individuals within a family, suggesting a possible relation of these variations to disease etiology. Variants include a R23M alteration in two affected half brothers which falls within the MBD domain of the MBD3 protein, as well as a frameshift in MBD4 that is predicted to truncate almost half of the protein. These results suggest that rare cases of autism may be influenced by mutations in members of the dynamic MBD protein family

A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome

Mutations in MECP2, encoding methyl CpG-binding protein 2, cause Rett syndrome, the most severe autism spectrum disorder. Re-expressing Mecp2 in symptomatic Mecp2-null mice markedly improves function and longevity, providing hope that therapeutic intervention is possible in humans. To identify pathways in disease pathology for therapeutic intervention, we carried out a dominant N-ethyl-N-nitrosourea (ENU) mutagenesis suppressor screen in Mecp2-null mice and isolated five suppressors that ameliorate the symptoms of Mecp2 loss. We show that a stop codon mutation in Sqle, encoding squalene epoxidase, a rate-limiting enzyme in cholesterol biosynthesis, underlies suppression in one line. Subsequently, we also show that lipid metabolism is perturbed in the brains and livers of Mecp2-null male mice. Consistently, statin drugs improve systemic perturbations of lipid metabolism, alleviate motor symptoms and confer increased longevity in Mecp2 mutant mice. Our genetic screen therefore points to cholesterol homeostasis as a potential target for the treatment of patients with Rett syndrome.Christie M Buchovecky, Stephen D Turley, Hannah M Brown, Stephanie M Kyle, Jeffrey G McDonald, Benny Liu, Andrew A Pieper, Wenhui Huang, David M Katz, David W Russell, Jay Shendure & Monica J Justic

Positive Behavior Interventions: the Issue of Sustainability of Positive Effects

During the last decade, positive behavior interventions have resulted in improvement of school behavior and academic gains in a range of school settings worldwide. Recent studies identify sustainability of current positive behavior intervention programs as a major concern. The purpose of this article is to identify future direction for effective implementation of positive behavior interventions based on a comprehensive review of the current status of positive behavior interventions in terms of sustainability. The review will also examine implementation fidelity, as a factor that impacts upon sustainability. Literature reviewed in this study demonstrates that administrator support and professional development were the most frequently cited influential factors in previous research on sustainability of positive behavior interventions. In particular, the review highlights the significance of implementation fidelity at the classroom level for sustaining positive outcomes of positive behavior interventions over time. It is argued that in order to sustain positive effects of positive behavior intervention, future implementation efforts need to emphasize administrator support for the school team, ongoing high-quality professional development, and technical assistance. Moreover, a focus on coaching classroom-level implementation fidelity is of significant importance, as is the development and validation of evaluation tools for sustainability based on large-scale longitudinal international studies and more in-depth qualitative investigations

Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus-CA3 projection

Nuclear receptor corepressor 1 (NCOR1) and NCOR2 (also known as SMRT) regulate gene expression by activating histone deacetylase 3 through their deacetylase activation domain (DAD). We show that mice with DAD knock-in mutations have memory deficits, reduced anxiety levels, and reduced social interactions. Mice with NCOR1 and NORC2 depletion specifically in GABAergic neurons (NS-V mice) recapitulated the memory deficits and had reduced GABAA receptor subunit α2 (GABRA2) expression in lateral hypothalamus GABAergic (LHGABA) neurons. This was associated with LHGABA neuron hyperexcitability and impaired hippocampal long-term potentiation, through a monosynaptic LHGABA to CA3GABA projection. Optogenetic activation of this projection caused memory deficits, whereas targeted manipulation of LHGABA or CA3GABA neuron activity reversed memory deficits in NS-V mice. We describe de novo variants in NCOR1, NCOR2 or HDAC3 in patients with intellectual disability or neurodevelopmental disorders. These findings identify a hypothalamus-hippocampus projection that may link endocrine signals with synaptic plasticity through NCOR-mediated regulation of GABA signaling