Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability

Lin Li; Mohammad Ghorbani; Monika Weisz-Hubshman; Justine Rousseau; Isabelle Thiffault; Rhonda E Schnur; Catherine Breen; Renske Oegema; Marjan Mm Weiss; Quinten Waisfisz; Sara Welner; Helen Kingston; Jordan A Hills; Elles Mj Boon; Lina Basel-Salmon; Osnat Konen; Hadassa Goldberg-Stern; Lily Bazak; Shay Tzur; Jianliang Jin; Xiuli Bi; Michael Bruccoleri; Kirsty McWalter; Megan T Cho; Maria Scarano; G Bradley Schaefer; Susan S Brooks; Susan Starling Hughes; K L I van Gassen; Johanna M van Hagen; Tej K Pandita; Pankaj B Agrawal; Philippe M Campeau; Xiang-Jiao Yang

doi:10.1172/JCI131145

Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability

Lin Li, Mohammad Ghorbani, Monika Weisz-Hubshman, Justine Rousseau, Isabelle Thiffault, Rhonda E Schnur, Catherine Breen, Renske Oegema, Marjan Mm Weiss, Quinten Waisfisz, Sara Welner, Helen Kingston, Jordan A Hills, Elles Mj Boon, Lina Basel-Salmon, Osnat Konen, Hadassa Goldberg-Stern, Lily Bazak, Shay Tzur, Jianliang JinXiuli Bi, Michael Bruccoleri, Kirsty McWalter, Megan T Cho, Maria Scarano, G Bradley Schaefer, Susan S Brooks, Susan Starling Hughes, K L I van Gassen, Johanna M van Hagen, Tej K Pandita, Pankaj B Agrawal, Philippe M Campeau, Xiang-Jiao Yang

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

42 Scopus citations

Abstract

Epigenetic integrity is critical for many eukaryotic cellular processes. An important question is how different epigenetic regulators control development and impact disease. Lysine acetyltransferase 8 (KAT8) is critical for acetylation of histone H4 at lysine 16 (H4K16), an evolutionarily conserved epigenetic mark. It is unclear what roles KAT8 plays in cerebral development and human disease. Here, we report that cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus, along with improper neural stem and progenitor cell (NSPC) development. Mutant cerebrocortical neuroepithelia exhibited faulty proliferation, aberrant neurogenesis, massive apoptosis and scant H4K16 propionylation. Mutant NSPCs formed poor neurospheres, and pharmacological KAT8 inhibition abolished neurosphere formation. Moreover, we describe KAT8 variants in nine patients with intellectual disability, seizures, autism, dysmorphisms and other anomalies. The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation. Valproate was effective for treating epilepsy in at least two of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies nine individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy and other developmental anomalies.

Original language	English (US)
Journal	The Journal of clinical investigation
DOIs	https://doi.org/10.1172/JCI131145
State	E-pub ahead of print - Dec 3 2019

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10.1172/JCI131145

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Li, L., Ghorbani, M., Weisz-Hubshman, M., Rousseau, J., Thiffault, I., Schnur, R. E., Breen, C., Oegema, R., Weiss, M. M., Waisfisz, Q., Welner, S., Kingston, H., Hills, J. A., Boon, E. M., Basel-Salmon, L., Konen, O., Goldberg-Stern, H., Bazak, L., Tzur, S., ... Yang, X.-J. (2019). Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability. The Journal of clinical investigation. Advance online publication. https://doi.org/10.1172/JCI131145

Li, L, Ghorbani, M, Weisz-Hubshman, M, Rousseau, J, Thiffault, I, Schnur, RE, Breen, C, Oegema, R, Weiss, MM, Waisfisz, Q, Welner, S, Kingston, H, Hills, JA, Boon, EM, Basel-Salmon, L, Konen, O, Goldberg-Stern, H, Bazak, L, Tzur, S, Jin, J, Bi, X, Bruccoleri, M, McWalter, K, Cho, MT, Scarano, M, Schaefer, GB, Brooks, SS, Hughes, SS, van Gassen, KLI, van Hagen, JM, Pandita, TK, Agrawal, PB, Campeau, PM & Yang, X-J 2019, 'Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability', The Journal of clinical investigation. https://doi.org/10.1172/JCI131145

@article{868c5fb1813842beb7692986ce829b0b,

title = "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability",

abstract = "Epigenetic integrity is critical for many eukaryotic cellular processes. An important question is how different epigenetic regulators control development and impact disease. Lysine acetyltransferase 8 (KAT8) is critical for acetylation of histone H4 at lysine 16 (H4K16), an evolutionarily conserved epigenetic mark. It is unclear what roles KAT8 plays in cerebral development and human disease. Here, we report that cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus, along with improper neural stem and progenitor cell (NSPC) development. Mutant cerebrocortical neuroepithelia exhibited faulty proliferation, aberrant neurogenesis, massive apoptosis and scant H4K16 propionylation. Mutant NSPCs formed poor neurospheres, and pharmacological KAT8 inhibition abolished neurosphere formation. Moreover, we describe KAT8 variants in nine patients with intellectual disability, seizures, autism, dysmorphisms and other anomalies. The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation. Valproate was effective for treating epilepsy in at least two of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies nine individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy and other developmental anomalies.",

author = "Lin Li and Mohammad Ghorbani and Monika Weisz-Hubshman and Justine Rousseau and Isabelle Thiffault and Schnur, {Rhonda E} and Catherine Breen and Renske Oegema and Weiss, {Marjan Mm} and Quinten Waisfisz and Sara Welner and Helen Kingston and Hills, {Jordan A} and Boon, {Elles Mj} and Lina Basel-Salmon and Osnat Konen and Hadassa Goldberg-Stern and Lily Bazak and Shay Tzur and Jianliang Jin and Xiuli Bi and Michael Bruccoleri and Kirsty McWalter and Cho, {Megan T} and Maria Scarano and Schaefer, {G Bradley} and Brooks, {Susan S} and Hughes, {Susan Starling} and {van Gassen}, {K L I} and {van Hagen}, {Johanna M} and Pandita, {Tej K} and Agrawal, {Pankaj B} and Campeau, {Philippe M} and Xiang-Jiao Yang",

year = "2019",

month = dec,

day = "3",

doi = "10.1172/JCI131145",

language = "English (US)",

journal = "The Journal of clinical investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

}

TY - JOUR

T1 - Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability

AU - Li, Lin

AU - Ghorbani, Mohammad

AU - Weisz-Hubshman, Monika

AU - Rousseau, Justine

AU - Thiffault, Isabelle

AU - Schnur, Rhonda E

AU - Breen, Catherine

AU - Oegema, Renske

AU - Weiss, Marjan Mm

AU - Waisfisz, Quinten

AU - Welner, Sara

AU - Kingston, Helen

AU - Hills, Jordan A

AU - Boon, Elles Mj

AU - Basel-Salmon, Lina

AU - Konen, Osnat

AU - Goldberg-Stern, Hadassa

AU - Bazak, Lily

AU - Tzur, Shay

AU - Jin, Jianliang

AU - Bi, Xiuli

AU - Bruccoleri, Michael

AU - McWalter, Kirsty

AU - Cho, Megan T

AU - Scarano, Maria

AU - Schaefer, G Bradley

AU - Brooks, Susan S

AU - Hughes, Susan Starling

AU - van Gassen, K L I

AU - van Hagen, Johanna M

AU - Pandita, Tej K

AU - Agrawal, Pankaj B

AU - Campeau, Philippe M

AU - Yang, Xiang-Jiao

PY - 2019/12/3

Y1 - 2019/12/3

N2 - Epigenetic integrity is critical for many eukaryotic cellular processes. An important question is how different epigenetic regulators control development and impact disease. Lysine acetyltransferase 8 (KAT8) is critical for acetylation of histone H4 at lysine 16 (H4K16), an evolutionarily conserved epigenetic mark. It is unclear what roles KAT8 plays in cerebral development and human disease. Here, we report that cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus, along with improper neural stem and progenitor cell (NSPC) development. Mutant cerebrocortical neuroepithelia exhibited faulty proliferation, aberrant neurogenesis, massive apoptosis and scant H4K16 propionylation. Mutant NSPCs formed poor neurospheres, and pharmacological KAT8 inhibition abolished neurosphere formation. Moreover, we describe KAT8 variants in nine patients with intellectual disability, seizures, autism, dysmorphisms and other anomalies. The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation. Valproate was effective for treating epilepsy in at least two of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies nine individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy and other developmental anomalies.

AB - Epigenetic integrity is critical for many eukaryotic cellular processes. An important question is how different epigenetic regulators control development and impact disease. Lysine acetyltransferase 8 (KAT8) is critical for acetylation of histone H4 at lysine 16 (H4K16), an evolutionarily conserved epigenetic mark. It is unclear what roles KAT8 plays in cerebral development and human disease. Here, we report that cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus, along with improper neural stem and progenitor cell (NSPC) development. Mutant cerebrocortical neuroepithelia exhibited faulty proliferation, aberrant neurogenesis, massive apoptosis and scant H4K16 propionylation. Mutant NSPCs formed poor neurospheres, and pharmacological KAT8 inhibition abolished neurosphere formation. Moreover, we describe KAT8 variants in nine patients with intellectual disability, seizures, autism, dysmorphisms and other anomalies. The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation. Valproate was effective for treating epilepsy in at least two of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies nine individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy and other developmental anomalies.

U2 - 10.1172/JCI131145

DO - 10.1172/JCI131145

M3 - Article

C2 - 31794431

SN - 0021-9738

JO - The Journal of clinical investigation

JF - The Journal of clinical investigation

ER -

Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability

Abstract

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