In vivo epigenetic editing of Sema6a promoter reverses transcallosal dysconnectivity caused by C11orf46/Arl14ep risk gene

Cyril J. Peter; Atsushi Saito; Yuto Hasegawa; Yuya Tanaka; Mohika Nagpal; Gabriel Perez; Emily Alway; Sergio Espeso-Gil; Tariq Fayyad; Chana Ratner; Aslihan Dincer; Achla Gupta; Lakshmi Devi; John G. Pappas; François M. Lalonde; John A. Butman; Joan C. Han; Schahram Akbarian; Atsushi Kamiya

doi:10.1038/s41467-019-12013-y

In vivo epigenetic editing of Sema6a promoter reverses transcallosal dysconnectivity caused by C11orf46/Arl14ep risk gene

Cyril J. Peter, Atsushi Saito, Yuto Hasegawa, Yuya Tanaka, Mohika Nagpal, Gabriel Perez, Emily Alway, Sergio Espeso-Gil, Tariq Fayyad, Chana Ratner, Aslihan Dincer, Achla Gupta, Lakshmi Devi, John G. Pappas, François M. Lalonde, John A. Butman, Joan C. Han, Schahram Akbarian, Atsushi Kamiya

School of Medicine

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Many neuropsychiatric risk genes contribute to epigenetic regulation but little is known about specific chromatin-associated mechanisms governing the formation of neuronal connectivity. Here we show that transcallosal connectivity is critically dependent on C11orf46, a nuclear protein encoded in the chromosome 11p13 WAGR risk locus. C11orf46 haploinsufficiency was associated with hypoplasia of the corpus callosum. C11orf46 knockdown disrupted transcallosal projections and was rescued by wild type C11orf46 but not the C11orf46^R236H mutant associated with intellectual disability. Multiple genes encoding key regulators of axonal development, including Sema6a, were hyperexpressed in C11orf46-knockdown neurons. RNA-guided epigenetic editing of Sema6a gene promoters via a dCas9-SunTag system with C11orf46 binding normalized SEMA6A expression and rescued transcallosal dysconnectivity via repressive chromatin remodeling by the SETDB1 repressor complex. Our study demonstrates that interhemispheric communication is sensitive to locus-specific remodeling of neuronal chromatin, revealing the therapeutic potential for shaping the brain’s connectome via gene-targeted designer activators and repressor proteins.

Original language	English (US)
Article number	4112
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12013-y
State	Published - Dec 1 2019

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Biochemistry, Genetics and Molecular Biology(all)

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Peter, C. J., Saito, A., Hasegawa, Y., Tanaka, Y., Nagpal, M., Perez, G., Alway, E., Espeso-Gil, S., Fayyad, T., Ratner, C., Dincer, A., Gupta, A., Devi, L., Pappas, J. G., Lalonde, F. M., Butman, J. A., Han, J. C., Akbarian, S., & Kamiya, A. (2019). In vivo epigenetic editing of Sema6a promoter reverses transcallosal dysconnectivity caused by C11orf46/Arl14ep risk gene. Nature communications, 10(1), [4112]. https://doi.org/10.1038/s41467-019-12013-y

Peter, CJ, Saito, A , Hasegawa, Y, Tanaka, Y, Nagpal, M, Perez, G, Alway, E, Espeso-Gil, S, Fayyad, T, Ratner, C, Dincer, A, Gupta, A, Devi, L, Pappas, JG, Lalonde, FM, Butman, JA, Han, JC, Akbarian, S & Kamiya, A 2019, 'In vivo epigenetic editing of Sema6a promoter reverses transcallosal dysconnectivity caused by C11orf46/Arl14ep risk gene', Nature communications, vol. 10, no. 1, 4112. https://doi.org/10.1038/s41467-019-12013-y

@article{a63e122f87a9497da18953454723ee62,

title = "In vivo epigenetic editing of Sema6a promoter reverses transcallosal dysconnectivity caused by C11orf46/Arl14ep risk gene",

abstract = "Many neuropsychiatric risk genes contribute to epigenetic regulation but little is known about specific chromatin-associated mechanisms governing the formation of neuronal connectivity. Here we show that transcallosal connectivity is critically dependent on C11orf46, a nuclear protein encoded in the chromosome 11p13 WAGR risk locus. C11orf46 haploinsufficiency was associated with hypoplasia of the corpus callosum. C11orf46 knockdown disrupted transcallosal projections and was rescued by wild type C11orf46 but not the C11orf46R236H mutant associated with intellectual disability. Multiple genes encoding key regulators of axonal development, including Sema6a, were hyperexpressed in C11orf46-knockdown neurons. RNA-guided epigenetic editing of Sema6a gene promoters via a dCas9-SunTag system with C11orf46 binding normalized SEMA6A expression and rescued transcallosal dysconnectivity via repressive chromatin remodeling by the SETDB1 repressor complex. Our study demonstrates that interhemispheric communication is sensitive to locus-specific remodeling of neuronal chromatin, revealing the therapeutic potential for shaping the brain{\textquoteright}s connectome via gene-targeted designer activators and repressor proteins.",

author = "Peter, {Cyril J.} and Atsushi Saito and Yuto Hasegawa and Yuya Tanaka and Mohika Nagpal and Gabriel Perez and Emily Alway and Sergio Espeso-Gil and Tariq Fayyad and Chana Ratner and Aslihan Dincer and Achla Gupta and Lakshmi Devi and Pappas, {John G.} and Lalonde, {Fran{\c c}ois M.} and Butman, {John A.} and Han, {Joan C.} and Schahram Akbarian and Atsushi Kamiya",

note = "Funding Information: We thank Dr. Kazuhiro Ishii, Ms. Nicole Rangos, Mr. Akarsh Sharma, and Mr. Tomonori Matsushita for technical and intellectual assistance of experiments; Dr. Xiaolei Zhu, Ms. Aisa Moreno-Megui and Ms. Nada Redradjaja for a critical reading of the manuscript; Lee Blosser and Raffaello Cimbro for sorting cells by FACS; Dr. Elliot Androphy for providing NSC34 cells. This work was supported by DA041208 (A.K.), MH091230 (A.K.), AT008547 (A.K.), MH094268 (A.K.), JHU Catalyst Award (A.K.), MH104341 (S.A.), MH117790 (S.A.), the Brain & Behavior Research Foundation (A.K., S.A., A.S.), ZIAHD008898 (J.C.H.), an NIH Bench-to-Bedside Award (J.C.H), and S10OD016374 (Dr. Scot C. Kuo for use of confocal microscope LSM 700). Funding Information: Competing interests: J.C.H. is the recipient of an unrestricted research grant from Rhythm Pharmaceuticals. The other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

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doi = "10.1038/s41467-019-12013-y",

language = "English (US)",

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T1 - In vivo epigenetic editing of Sema6a promoter reverses transcallosal dysconnectivity caused by C11orf46/Arl14ep risk gene

AU - Peter, Cyril J.

AU - Saito, Atsushi

AU - Hasegawa, Yuto

AU - Tanaka, Yuya

AU - Nagpal, Mohika

AU - Perez, Gabriel

AU - Alway, Emily

AU - Espeso-Gil, Sergio

AU - Fayyad, Tariq

AU - Ratner, Chana

AU - Dincer, Aslihan

AU - Gupta, Achla

AU - Devi, Lakshmi

AU - Pappas, John G.

AU - Lalonde, François M.

AU - Butman, John A.

AU - Han, Joan C.

AU - Akbarian, Schahram

AU - Kamiya, Atsushi

N1 - Funding Information: We thank Dr. Kazuhiro Ishii, Ms. Nicole Rangos, Mr. Akarsh Sharma, and Mr. Tomonori Matsushita for technical and intellectual assistance of experiments; Dr. Xiaolei Zhu, Ms. Aisa Moreno-Megui and Ms. Nada Redradjaja for a critical reading of the manuscript; Lee Blosser and Raffaello Cimbro for sorting cells by FACS; Dr. Elliot Androphy for providing NSC34 cells. This work was supported by DA041208 (A.K.), MH091230 (A.K.), AT008547 (A.K.), MH094268 (A.K.), JHU Catalyst Award (A.K.), MH104341 (S.A.), MH117790 (S.A.), the Brain & Behavior Research Foundation (A.K., S.A., A.S.), ZIAHD008898 (J.C.H.), an NIH Bench-to-Bedside Award (J.C.H), and S10OD016374 (Dr. Scot C. Kuo for use of confocal microscope LSM 700). Funding Information: Competing interests: J.C.H. is the recipient of an unrestricted research grant from Rhythm Pharmaceuticals. The other authors declare no competing interests. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Many neuropsychiatric risk genes contribute to epigenetic regulation but little is known about specific chromatin-associated mechanisms governing the formation of neuronal connectivity. Here we show that transcallosal connectivity is critically dependent on C11orf46, a nuclear protein encoded in the chromosome 11p13 WAGR risk locus. C11orf46 haploinsufficiency was associated with hypoplasia of the corpus callosum. C11orf46 knockdown disrupted transcallosal projections and was rescued by wild type C11orf46 but not the C11orf46R236H mutant associated with intellectual disability. Multiple genes encoding key regulators of axonal development, including Sema6a, were hyperexpressed in C11orf46-knockdown neurons. RNA-guided epigenetic editing of Sema6a gene promoters via a dCas9-SunTag system with C11orf46 binding normalized SEMA6A expression and rescued transcallosal dysconnectivity via repressive chromatin remodeling by the SETDB1 repressor complex. Our study demonstrates that interhemispheric communication is sensitive to locus-specific remodeling of neuronal chromatin, revealing the therapeutic potential for shaping the brain’s connectome via gene-targeted designer activators and repressor proteins.

AB - Many neuropsychiatric risk genes contribute to epigenetic regulation but little is known about specific chromatin-associated mechanisms governing the formation of neuronal connectivity. Here we show that transcallosal connectivity is critically dependent on C11orf46, a nuclear protein encoded in the chromosome 11p13 WAGR risk locus. C11orf46 haploinsufficiency was associated with hypoplasia of the corpus callosum. C11orf46 knockdown disrupted transcallosal projections and was rescued by wild type C11orf46 but not the C11orf46R236H mutant associated with intellectual disability. Multiple genes encoding key regulators of axonal development, including Sema6a, were hyperexpressed in C11orf46-knockdown neurons. RNA-guided epigenetic editing of Sema6a gene promoters via a dCas9-SunTag system with C11orf46 binding normalized SEMA6A expression and rescued transcallosal dysconnectivity via repressive chromatin remodeling by the SETDB1 repressor complex. Our study demonstrates that interhemispheric communication is sensitive to locus-specific remodeling of neuronal chromatin, revealing the therapeutic potential for shaping the brain’s connectome via gene-targeted designer activators and repressor proteins.

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In vivo epigenetic editing of Sema6a promoter reverses transcallosal dysconnectivity caused by C11orf46/Arl14ep risk gene

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