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The Evolving Role of Mecp2 in Rett Syndrome and Autism

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The Evolving Role of Mecp2 in Rett Syndrome and Autism ?? The Evolving Role of MeCP2 in Rett Syndrome and Autism Janine LaSalle, Ph.D Medical Microbiology and Immunology Rowe Program in Human Genetics UC Davis School of Medicine Epigenetics and Autism What’s the connection? AUTISM ? MeCP2 Rett Syndrome Angelman, Prader-Willi, MECP2 mutation 15q syndromes 15q11-13 deficiency or duplication Autism • Complex developmental disorder that usually appears 1-3 yr • Deficits in social interaction and communication • Repetitive stereotyped behavior and abnormal preoccupations • Complex genetic etiology influenced by environmental factors Rett Syndrome (RTT) • RTT is the only one of the five Pervasive Developmental Disorders with a known genetic cause • X-linked dominant, ~80% MECP2 mutation • Neurodevelopmental regression around 6 to 18 months of age • Mental retardation, ataxia, loss of purposeful hand movements, loss of vocalization skills, seizures Angelman and Prader-willi syndromes Imprinted disorders caused by 15q11-13 deletions or deficiency AS: Maternal 15q11-13 QuickTime™ and a QuickTime™ and a TIFF (Uncompressed) decompressor TIFF (Uncompressed) decompressor are needed to see this picture. deletion, paternal disomy, are needed to see this picture. maternal UBE3A mutation, imprinting defects PWS: Paternal 15q11-13 deletion, maternal disomy, imprinting defects 15q duplication syndrome isodicentric chromosome 15 • Cytogenetic abnormality of proximal 15q • interstitial duplication or idic 15 • Hypotonia, small stature • Autistic features, anxiety, seizures • Defects in sensory processing, language, and attention QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. idic 15 QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. interstitial duplication Overlap between autism, Rett and 15q11-13 syndromes Phenotypic overlap • stereotypic behaviors • language impairments • seizures (RTT, AS, 20-30% autism) • delayed postnatal onset, regression (RTT and autism) • mental retardation (RTT, AS, ~80% autism) • sleep abnormalities Evidence for genetic overlap • MECP2 mutations in rare cases of autism • MECP2 mutations in rare cases with AS phenotype • 15q11-13 maternal duplications in 1-3% of autism • 15q11-13 rearrangements in 3 RTT cases • linkage to 15q11-13 loci in autism families Evidence for epigenetic overlap between autism, RTT, and 15q • MeCP2 expression is significantly reduced in 79% of autism post-mortem brain samples • Methylation of the MECP2 promoter correlates with reduced expression in male autism brain samples • GABRB3 expression (15q11-13) is significantly reduced in 56% of autism post-mortem brain samples • Biallelic expression levels of GABRB3 are epigenetically dysregulated in Rett and autism postmortem brain • Homologous pairing of 15q11-13 in mature neurons is deficient in RTT, autism, and AS Ravi Nagarajan Amber Hogart Karen Thatcher GGG student GGG student GGG student Methyl CpG Binding Protein 2 • Binds methylated CpG dinucleotides • Transcriptional repressor • Xq28 (X chromosome inactivation) • Complex developmental regulation (Bird and Wolffe, Cell 1999) A A A A A A ATG ATG A A 5.3 kb 5’ 69 bp 124 bp 3’ 3’ UTR 76 kb MeCP2 is a marker for mature neurons in the post-natal mammalian brain Sytox Green Anti-MeCP2 Evolving models of MeCP2 come full circle HDAC OFF Sin3a MeCP2 Repressor Model M MeCP2 e MeCP2 ON C MeCP2 P M coactivators 2 MeCP2 e C P 2 M eC MeCP2 CREB1 M P2 e C MeCP2 P 2 MeCP2 Transcriptional activator model ?? MeCP2 Structural Model Splicing Chromatin ON Remodeling 2 P 2 ATRX C MeCP2 YB-1 P e C 2 e P M C Brahma M e M Loop and recruit model Active gene modulator model LaSalle and Yasui, Epigenomics, in press The majority of MeCP2 bound promoters are on expressed genes Yasui et al, PNAS, 2007 MeCP2 is bound to promoters of highly expressed genes Yasui et al, PNAS, 2007 Highly methylated promoters are not bound by MeCP2 Yasui et al, PNAS, 2007 Example: MeDIP + MeCP2 and Pol2 ChIP at HOXA locus MeDIP MeCP2 Pol2 HOXA1 HOXA2 HOXA3 HOXA4 HOXA5 HOXA6 HOXA7 HOXA9 HOXA10 HOXA11 HOXA13 More examples from Nimblegen promoter arrays for MeDIP, MeCP2, and Pol2 QuickTime™ and a decompressor are needed to see this picture. POU5F1 (OCT4) QuickTime™ and a decompressor are needed to see this picture. NOL1 GAPDH CHD4 Micrococcal nuclease fractionation of chromatin shows MeCP2 primarily in active fraction QuickTime™ and a decompressor are needed to see this picture. Western blot DNA dot-blot QuickTime™ and a decompressor QuickTime™ and a are needed to see this picture. decompressor are needed to see this picture. Mike Gonzales, unpublished MeCP2 localizes to both inert nuclear heterochromatin as well as non- heterochromatic regions Mecp2 +/y Mecp2 -/y Anti-MeCP2 DAPI Sub-nuclear localization patterns of MeCP2 are consistent with dual functions in repression and activation The majority of MeCP2 binding sites are intergenic or intronic Yasui et al, PNAS, 2007 ChIP-chip analysis of established MeCP2 target genes Yasui et al, PNAS, 2007 MeCP2 ChIP-chip analysis of imprinted region 15q11-13 chr15 20000000 25000000 30000000 L3 Sites POTE15 NIPA2 NDN SNRPN GABRB3 NDNL2 SGNE1 Genes C15orf2 OCA2 TRPM1 NIPA1 SNURF HERC2 TJP1 KLF13 OR4M2 MKRN3 OR4N4 GREM1 C15orf16 RYR3 CHRFAM7A CHRNA7 TUBGCP5 UBE3A CYFIP1 ATP10A APBA2 MTMR10 Previously described and validated Validated 30100000 30200000 L3 sites CHRNA7 BC087571 CpG islands Validated in human Yasui et al, PNAS, 2007 MeCP2 target genes at closer examination Active genes that MeCP2 represses through intergenic sites JUNB ID1 Active genes that MeCP2 activates through intronic enhancers EGR2 GABRB3 ChIP-chip analysis of 19p13.2 and JUNB Yasui et al, PNAS, 2007 Methylation of upstream binding site for are needed to see this picture. QuickTime™ and a decompressor ID1 is upregulated in Peddada et al, 2006 29644000 3.5 29644800 -2.0 3.5 DNA methylation patterns do Mecp2 29645600 not change with differentiation -2.0 Site 1 ID1 3.5Log2 Ratio 29646400 29647200 -/y -2.0 3.5 with unmethylated promoter brain 29648000 -2.0 29646600 29649600 29650400 29651200 MeCP2 binding Site 29652000 3.5 Site -1 [659 bp,10CpG] Log2 Ratio -10 Kb Upstream -2.0 29652800 29645600 29653600 29646000 29654400 -10.1kb 29655200 * 29646400 UD -10.37kb ** ** Site 2 29656000 29656800 -10.75kb ID1 D -UT 296576000 MeCP2 ID1 PromoterSite -2 UD Pol2 3.5 -Log2 2.0 Ratio 29656400 D -UT MeCP2 29656600 Genomic tiling array * * * -1100bp Pol2 - 666bp 29656800 ID1 - 657bp Promoter * p * * -109b +1 Promoter tiling array ID1 ** * UD * * S. Peddada, unpublished D -UT Reciprocal regulation of MECP2 and EGR2 intronic enhancer QuickTime™ and a decompressor are needed to see this picture. QuickTime™ and a decompressor are needed to see this picture. EGR2 MECP2 EGR2 Neuronal maturation MeCP2 Swanberg et al, 2009 15q11-13 GABA A receptor subunit GABRB3 has MeCP2 in intronic enhancer for homologous pairing and biallelic expression QuickTime™ and a decompressor are needed to see this picture. MeCP2 intronic binding predicted to act as a pairing factor for optimal maternal expression QuickTime™ and a decompressor are needed to see this picture. Hogart et al, HMG, 2007 “Dimmer switch” model of MeCP2 as long range modulator of gene expression ON OFF HDAC OFF ON Sin3a MeCP2 LO HI MeCP2 Textbook Structure enzymatic model Location as “off” switch Loop Recruit Modulator rather than silencer Future goals for improved understanding of MeCP2 • Characterize and develop reagents for investigating all MeCP2 post-translational modifications • Characterize MeCP2 alternative isoforms, particularly MeCP2e1 in brain • Genome-wide ChIP-seq in primary neurons • Correlate MeCP2 binding sites with DNA methylation, histone marks, and gene expression genome-wide Genomic map of the 15q11-13 deletion/duplication disorders Cen BP2 BP3 BP4 BP5 BP1 Weiss et al., 2008 autism Class 3B idic(15) Class 5A idic(15) PWS/AS Class I PWS/AS deletions/ int dups Class II PWS/AS deletions/ int dups 15q13.3 microduplication epilesy, autism, (Miller, 2008; Christian, 2008) schizophrenia, 15q11.2 microduplication control (Stefansson, 2008) 15q13.3 microdeletion (Sharp, 2008; Pagnamenta, 2008; Miller, 2008; Helbig, 2009; ISRC, 2008; Stefansson 2008)) Imprinted and neuronal regulation of 15q11-13 Paternally Expressed CEN Maternally MKRN3 Expressed DNA FISH MAGEL2 Probes NDN PWS- ICR SNRPN expressed in neurons AS-ICR 175kb HBII -13 HBII- 85 170kb HBII -52 161kb UBE3A- AS UBE3A ATP10A TEL Chromatin decondensation of Murine 7qC TEL Mkrn3 DNA FISH Probes Magel2 Ndn neuron-specific IC 207kb paternal neuronal transcript Snrpn MBII -13 MBII -85 Snrpn Paternal signal ~5.1µm (average) 888kb 266.4µm/5.1µm = 52.2:1 packing ratio 1.3x more compact then a 30nm fiberSnrpn MBII -52 DAPI Maternal signal ~1.1µm (average) 5’ of 3’ of 266.4µm/1.1µm = 242.2:1 packing ratio to -Ube3a 6x more compact then a 30nm fiber Snrpn Ube3a -AS Atp10a Ube3a Ube3a Atp10a 206kb is CEN Snrpn Thymus Snrpn Brain -Ube3a -Ube3a Paternal Snrpn-Ube3a allele decondensation is developmentally regulated and correlates to nucleolar enlargement during neuronal maturation MBII-85 RNA FISH signal(µm) length Ube3a P21 P70 - Snrpn MBII-85 RNA FISH fluorescence FISH (pixel fluorescence intensity) RNA MBII-85 6 P1d 5 P14d Snrpn-Ube3a 4 3 2 Length (µm) Length 1 Length(microns) 0 Maternal Paternal Nuclear Nucleolar E15 P1 P21 P70 signal signal radius diameter P-value 3x10 -10 8x10 -33 2x10 -21 1x10 -15 Transcription is required for paternal Snrpn-Ube3a chromatin decondensation del35kb Hs Mouse model 1 +/PWS-IC PWS-IC /+ Mouse model 2 Paternal
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