Extra-coding RNAs regulate neuronal DNA methylation dynamics

Katherine E. Savell; Nancy V.N. Gallus; Rhiana C. Simon; Jordan A. Brown; Jasmin S. Revanna; Mary Katherine Osborn; Esther Y. Song; John J. O'Malley; Christian T. Stackhouse; Allison Norvil; Humaira Gowher; J. David Sweatt; Jeremy J. Day

doi:10.1038/ncomms12091

Extra-coding RNAs regulate neuronal DNA methylation dynamics

Katherine E. Savell, Nancy V.N. Gallus, Rhiana C. Simon, Jordan A. Brown, Jasmin S. Revanna, Mary Katherine Osborn, Esther Y. Song, John J. O'Malley, Christian T. Stackhouse, Allison Norvil, Humaira Gowher, J. David Sweatt, Jeremy J. Day

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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.

Original language	English
Article number	12091
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12091
State	Published - Jul 7 2016

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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.",

author = "Savell, {Katherine E.} and Gallus, {Nancy V.N.} and Simon, {Rhiana C.} and Brown, {Jordan A.} and Revanna, {Jasmin S.} and Osborn, {Mary Katherine} and Song, {Esther Y.} and O'Malley, {John J.} and Stackhouse, {Christian T.} and Allison Norvil and Humaira Gowher and Sweatt, {J. David} and Day, {Jeremy J.}",

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AU - Savell, Katherine E.

AU - Gallus, Nancy V.N.

AU - Simon, Rhiana C.

AU - Brown, Jordan A.

AU - Revanna, Jasmin S.

AU - Osborn, Mary Katherine

AU - Song, Esther Y.

AU - O'Malley, John J.

AU - Stackhouse, Christian T.

AU - Norvil, Allison

AU - Gowher, Humaira

AU - Sweatt, J. David

AU - Day, Jeremy J.

PY - 2016/7/7

Y1 - 2016/7/7

N2 - 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.

AB - 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.

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JO - Nature communications

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Extra-coding RNAs regulate neuronal DNA methylation dynamics

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