title: ATRX promotes gene expression by facilitating transcriptional elongation through guanine-rich coding regions.
abstract: ATRX is a chromatin remodeling protein involved in deposition of the histone variant H3.3 at telomeres and pericentromeric heterochromatin. It also influences the expression level of specific genes; however, deposition of H3.3 at transcribed genes is currently thought to occur independently of ATRX. We focused on a set of genes, including the autism susceptibility gene Neuroligin 4 (Nlgn4), that exhibit decreased expression in ATRX-null cells to investigate the mechanisms used by ATRX to promote gene transcription. Overall TERRA levels, as well as DNA methylation and histone modifications at ATRX target genes are not altered and thus cannot explain transcriptional dysregulation. We found that ATRX does not associate with the promoter of these genes, but rather binds within regions of the gene body corresponding to high H3.3 occupancy. These intragenic regions consist of guanine-rich DNA sequences predicted to form non-B DNA structures called G-quadruplexes during transcriptional elongation. We demonstrate that ATRX deficiency corresponds to reduced H3.3 incorporation and stalling of RNA polymerase II at these G-rich intragenic sites. These findings suggest that ATRX promotes the incorporation of histone H3.3 at particular transcribed genes and facilitates transcriptional elongation through G-rich sequences. The inability to transcribe genes such as Nlgn4 could cause deficits in neuronal connectivity and cognition associated with ATRX mutations in humans.
authors.affiliation: Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada N6A 5C1, Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada N6A 5C1 Children's Health Research Institute, London, Ontario, Canada N6C 2V5.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Levy
authors.affiliation: Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada N6A 5C1, Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada N6A 5C1 Children's Health Research Institute, London, Ontario, Canada N6C 2V5.
authors.forename: Kristin D
authors.initials: KD
authors.lastname: Kernohan
authors.affiliation: Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada N6A 5C1, Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada N6A 5C1 Children's Health Research Institute, London, Ontario, Canada N6C 2V5.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada N6A 5C1, Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada N6A 5C1 Children's Health Research Institute, London, Ontario, Canada N6C 2V5 nberube@uwo.ca.
authors.forename: Nathalie G
authors.initials: NG
authors.lastname: Bérubé
mesh_terms: D000818:Animals; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D054856:G-Quadruplexes; D005786:Gene Expression Regulation; D006147:Guanine / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016366:Open Reading Frames; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D000075924:X-linked Nuclear Protein; D017085:alpha-Thalassemia / Q000196:embryology / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; D006657:Histones; D009687:Nuclear Proteins; D006147:Guanine; D004265:DNA Helicases; C490462:Atrx protein, mouse; D000075924:X-linked Nuclear Protein