title: 82-kDa choline acetyltransferase and SATB1 localize to β-amyloid induced matrix attachment regions.
abstract: The M-transcript of human choline acetyltransferase (ChAT) produces an 82-kDa protein (82-kDa ChAT) that concentrates in nuclei of cholinergic neurons. We assessed the effects of acute exposure to oligomeric amyloid-β1-42 (Aβ1-42) on 82-kDa ChAT disposition in SH-SY5Y neural cells, finding that acute exposure to Aβ1-42 results in increased association of 82-kDa ChAT with chromatin and formation of 82-kDa ChAT aggregates in nuclei. When measured by chromatin immunoprecipitation with next-generation sequencing (ChIP-seq), we identified that Aβ1-42-exposure increases 82-kDa ChAT association with gene promoters and introns. The Aβ1-42-induced 82-kDa ChAT aggregates co-localize with special AT-rich binding protein 1 (SATB1), which anchors DNA to scaffolding/matrix attachment regions (S/MARs). SATB1 had a similar genomic association as 82-kDa ChAT, with both proteins associating with synapse and cell stress genes. After Aβ1-42 -exposure, both SATB1 and 82-kDa ChAT are enriched at the same S/MAR on the APP gene, with 82-kDa ChAT expression attenuating an increase in an isoform-specific APP mRNA transcript. Finally, 82-kDa ChAT and SATB1 have patterned genomic association at regions enriched with S/MAR binding motifs. These results demonstrate that 82-kDa ChAT and SATB1 play critical roles in the response of neural cells to acute Aβ-exposure.
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine &Dentistry, University of Western Ontario, London, Ontario, N6A 5C1 Canada.|Molecular Medicine Group, Robarts Research Institute, University of Western Ontario, London, Ontario, N6A 5C1 Canada.
authors.forename: Warren
authors.initials: W
authors.lastname: Winick-Ng
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine &Dentistry, University of Western Ontario, London, Ontario, N6A 5C1 Canada.|Molecular Medicine Group, Robarts Research Institute, University of Western Ontario, London, Ontario, N6A 5C1 Canada.
authors.forename: Fabiana A
authors.initials: FA
authors.lastname: Caetano
authors.affiliation: London Health Sciences Centre, London, Ontario, N6A 5W9 Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Winick-Ng
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine &Dentistry, University of Western Ontario, London, Ontario, N6A 5C1 Canada.|Molecular Medicine Group, Robarts Research Institute, University of Western Ontario, London, Ontario, N6A 5C1 Canada.
authors.forename: Trevor M
authors.initials: TM
authors.lastname: Morey
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine &Dentistry, University of Western Ontario, London, Ontario, N6A 5C1 Canada.
authors.forename: Bryan
authors.initials: B
authors.lastname: Heit
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine &Dentistry, University of Western Ontario, London, Ontario, N6A 5C1 Canada.|Molecular Medicine Group, Robarts Research Institute, University of Western Ontario, London, Ontario, N6A 5C1 Canada.
authors.forename: R Jane
authors.initials: RJ
authors.lastname: Rylett
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007438:Introns / Q000187:drug effects; D036961:Matrix Attachment Region Binding Proteins / Q000378:metabolism*; D045170:Matrix Attachment Regions / Q000187:drug effects*; D008970:Molecular Weight; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D036961:Matrix Attachment Region Binding Proteins; C076189:SATB1 protein, human; D002795:Choline O-Acetyltransferase