Dynamic Changes in Histone H3 Lysine 9 Acetylation Localization Patterns During Neuronal Maturation Require MeCP2

Medical Microbiology and Immunology, Rowe Program in Human Genetics, School of Medicine, One Shields Ave, University of California, Davis, CA 95616, USA.
Epigenetics: official journal of the DNA Methylation Society (Impact Factor: 4.78). 01/2006; 1(1):24-31. DOI: 10.4161/epi.1.1.2339
Source: PubMed


Mutations within the gene encoding methyl CpG binding protein 2 (MECP2) cause the autism-spectrum neurodevelopmental disorder Rett Syndrome (RTT). MECP2 recruits histone deacetylase to methylated DNA and acts as a long-range regulator of methylated genes. Despite ubiquitous MECP2 expression, the phenotype of RTT and the Mecp2-deficient mouse is largely restricted to the postnatal brain. Since Mecp2-deficient mice have a defect in neuronal maturation, we sought to understand how MECP2/Mecp2 mutations globally affect histone modifications during postnatal brain development by an immunofluorescence approach. Using an antibody specific to acetylated histone H3 lysine 9 (H3K9ac), a bright punctate nuclear staining pattern was observed as MECP2 expression increased in early postnatal neuronal nuclei. As neurons matured in juvenile and adult brain samples, the intensity of H3K9ac staining was reduced. Mecp2-deficient mouse and RTT cerebral neurons lacked this developmental reduction in H3K9ac staining compared to age-matched controls, resulting in a significant increase in neuronal nuclei with bright H3K9ac punctate staining. In contrast, trimethylated histone H3 lysine 9 (H3K9me3) localized to heterochromatin independent of MeCP2, but showed significantly reduced levels in Mecp2 deficient mouse and RTT brain. Autism brain with reduced MECP2 expression displayed similar histone H3 alterations as RTT brain. These observations suggest that MeCP2 regulates global histone modifications during a critical postnatal stage of neuronal maturation. These results have implications for understanding the molecular pathogenesis of RTT and autism in which MECP2 mutation or deficiency corresponds with arrested neurodevelopment.

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Available from: Janine M Lasalle
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    • "Deficient homologous pairing of 15q11.2–13 has been identified in brains of patients with Rett syndrome and autism [Samaco et al., 2005; Thatcher and LaSalle, 2006]. Not only are ASD frequent among patients with 15q11–13 syndromes, but, reversely, genetic abnormalities of this region are an important cause of ASD, accounting for approximately 1% of cases. "
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    ABSTRACT: Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disabilities with various etiologies, but with a heritability estimate of more than 90%. Although the strong correlation between autism and genetic factors has been long established, the exact genetic background of ASD remains unclear. A number of genetic syndromes manifest ASD at higher than expected frequencies compared to the general population. These syndromes account for more than 10% of all ASD cases and include tuberous sclerosis, fragile X, Down, neurofibromatosis, Angelman, Prader-Willi, Williams, Duchenne, etc. Clinicians are increasingly required to recognize genetic disorders in individuals with ASD, in terms of providing proper care and prognosis to the patient, as well as genetic counseling to the family. Vice versa, it is equally essential to identify ASD in patients with genetic syndromes, in order to ensure correct management and appropriate educational placement. During investigation of genetic syndromes, a number of issues emerge: impact of intellectual disability in ASD diagnoses, identification of autistic subphenotypes and differences from idiopathic autism, validity of assessment tools designed for idiopathic autism, possible mechanisms for the association with ASD, etc. Findings from the study of genetic syndromes are incorporated into the ongoing research on autism etiology and pathogenesis; different syndromes converge upon common biological backgrounds (such as disrupted molecular pathways and brain circuitries), which probably account for their comorbidity with autism. This review paper critically examines the prevalence and characteristics of the main genetic syndromes, as well as the possible mechanisms for their association with ASD. © 2013 Wiley Periodicals, Inc.
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    • "On the other hand, a study utilizing quantitative immunofluorescence for H3K9me3 found a generalized decrease in Mecp2 deficient neuronal nuclei, although the punctate staining of heterochromatic foci was preserved in the mutants (Thatcher and LaSalle, 2006). Likewise, no consistent changes in global histone acetylation were reported in Mecp2/MECP2 deficient brain (Shahbazian et al., 2002a; Thatcher and LaSalle, 2006; Urdinguio et al., 2007), blood cells, or cell lines (Balmer et al., 2002; Kaufmann et al., 2005; Wan et al., 2001), and it remains possible that this variation may be in part due to differences in the genetic background and type of Mecp2/MECP2 mutations, or even the specific histone molecules or residues examined. "
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    ABSTRACT: Rett syndrome (RTT, OMIM # 312750), a neurodevelopmental disorder of early childhood, is primarily caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2). Various molecular functions have been ascribed to MECP2, including the regulation of histone modifications associated with repressive chromatin remodeling, but the role of these mechanisms for the pathophysiology of RTT remains unclear. Here, we explore whether or not neuronal expression of the histone H3-lysine 9 specific methyl-transferase, Setdb1 (Set domain, bifurcated 1)/Eset/Kmt1e, which is normally present only at low levels in differentiated neurons, rescues the RTT-like phenotype of Mecp2-deficient mice. A myc-tagged Setdb1 cDNA was expressed through the tau locus for ubiquitous expression in CNS neurons, or under control of the calcium/calmodulin-dependent protein kinase II (CK) promoter to selectively target postmitotic neurons in forebrain. However, the CK-Setdb1 transgene lead to an enhanced neurological deficit, and the tauSetdb1 allele further shortened life span of mice with a brain-wide deletion of Mecp2 during prenatal development. In contrast, no neurological deficits or premature death was observed in CK-Setdb1 and tauSetdb1 mice expressing wildtype Mecp2. However, levels of trimethylated H3K9 at pericentromeric repeats were fully maintained in differentiated neurons from symptomatic Mecp2 null mutant mice. Based on these results, we draw two conclusions: First, neuronal chromatin in RTT brain is not affected by a generalized deficit in H3K9 trimethylation. Second, artificial up-regulation of this repressive chromatin mark via Setdb1 gene delivery specifically to neurons is harmful for the Mecp2-deficient brain. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
    Full-text · Article · Jun 2011 · Neuropharmacology
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    • "Chromocenters and nucleoli are intimately linked as chromocenters consist of transcriptionally silent ribosomal DNA (rDNA) and nucleoli contain chromatin remodeling proteins involved in the formation of heterochromatin domains (Akhmanova et al., 2000; Caperta et al., 2007; Guetg et al., 2010; Santoro et al., 2002). Neuronal nuclei undergo dynamic changes in compaction and histone deacetylation during postnatal neuronal maturation and MeCP2 has been shown to mediate changes to the local chromatin structure (Ishibashi et al., 2008; Nikitina et al., 2007a; Nikitina et al., 2007b; Thatcher and LaSalle, 2006). Brero et al. (2005) investigated Neurobiology of Disease xxx (2011) xxx–xxx Abbreviations: MeCP2, methyl-CpG binding protein 2; MeCP2e1, isoform of MeCP2; MBD, methyl-binding domain; RTT, Rett syndrome; DIV, days in vitro; rDNA, ribosomal DNA. "
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    ABSTRACT: Mutations in MECP2, encoding methyl CpG binding protein 2, cause the neurodevelopmental disorder Rett syndrome. MeCP2 is an abundant nuclear protein that binds to chromatin and modulates transcription in response to neuronal activity. Prior studies of MeCP2 function have focused on specific gene targets of MeCP2, but a more global role for MeCP2 in neuronal nuclear maturation has remained unexplored. MeCP2 levels increase during postnatal brain development, coinciding with dynamic changes in neuronal chromatin architecture, particularly detectable as changes in size, number, and location of nucleoli and perinucleolar heterochromatic chromocenters. To determine a potential role for MeCP2 in neuronal chromatin maturational changes, we measured nucleoli and chromocenters in developing wild-type and Mecp2-deficient mouse cortical sections, as well as mouse primary cortical neurons and a human neuronal cell line following induced maturation. Mecp2-deficient mouse neurons exhibited significant differences in nucleolar and chromocenter number and size, as more abundant, smaller nucleoli in brain and primary neurons compared to wild-type, consistent with delayed neuronal nuclear maturation in the absence of MeCP2. Primary neurons increased chromocenter size following depolarization in wild-type, but not Mecp2-deficient cultures. Wild-type MECP2e1 over-expression in human SH-SY5Y cells was sufficient to induce significantly larger nucleoli, but not a T158M mutation of the methyl-binding domain. These results suggest that, in addition to the established role of MeCP2 in transcriptional regulation of specific target genes, the global chromatin-binding function of MeCP2 is essential for activity-dependent global chromatin dynamics during postnatal neuronal maturation.
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