title: Extra-coding RNAs regulate neuronal DNA methylation dynamics.
abstract: Epigenetic mechanisms such as DNA methylation are essential regulators of the function and information storage capacity of neurons. DNA methylation is highly dynamic in the developing and adult brain, and is actively regulated by neuronal activity and behavioural experiences. However, it is presently unclear how methylation status at individual genes is targeted for modification. Here, we report that extra-coding RNAs (ecRNAs) interact with DNA methyltransferases and regulate neuronal DNA methylation. Expression of ecRNA species is associated with gene promoter hypomethylation, is altered by neuronal activity, and is overrepresented at genes involved in neuronal function. Knockdown of the Fos ecRNA locus results in gene hypermethylation and mRNA silencing, and hippocampal expression of Fos ecRNA is required for long-term fear memory formation in rats. These results suggest that ecRNAs are fundamental regulators of DNA methylation patterns in neuronal systems, and reveal a promising avenue for therapeutic targeting in neuropsychiatric disease states.
authors.affiliation: Department of Neurobiology, McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Savell
authors.affiliation: Department of Neurobiology, McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Nancy V N
authors.initials: NV
authors.lastname: Gallus
authors.affiliation: Department of Neurobiology, McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Rhiana C
authors.initials: RC
authors.lastname: Simon
authors.affiliation: Department of Neurobiology, McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Jordan A
authors.initials: JA
authors.lastname: Brown
authors.affiliation: Department of Neurobiology, McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Jasmin S
authors.initials: JS
authors.lastname: Revanna
authors.affiliation: Department of Neurobiology, McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Mary Katherine
authors.initials: MK
authors.lastname: Osborn
authors.affiliation: Department of Neurobiology, McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Esther Y
authors.initials: EY
authors.lastname: Song
authors.affiliation: Department of Neurobiology, McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Malley
authors.affiliation: Department of Neurobiology, McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Christian T
authors.initials: CT
authors.lastname: Stackhouse
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Norvil
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Humaira
authors.initials: H
authors.lastname: Gowher
authors.affiliation: Department of Neurobiology, McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: J David
authors.initials: JD
authors.lastname: Sweatt
authors.affiliation: Department of Neurobiology, McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Day
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000378:metabolism*; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005239:Fear / Q000502:physiology; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D016761:Oncogene Proteins v-fos / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013238:Stereotaxic Techniques
chemical_list: D016376:Oligonucleotides, Antisense; D016761:Oncogene Proteins v-fos; D012333:RNA, Messenger