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 M.M. Weiss; Quinten Waisfisz; Sara Welner; Helen Kingston; Jordan A. Hills; Elles M.J. 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 M.M. Weiss, Quinten Waisfisz, Sara Welner, Helen Kingston, Jordan A. Hills, Elles M.J. 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

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26 Scopus citations

Abstract

Epigenetic integrity is critical for many eukaryotic cellular processes. An important question is how different epigenetic regulators control development and influence 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 9 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 2 of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies 9 individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy, and other developmental anomalies.

Original language	English
Pages (from-to)	1431-1445
Number of pages	15
Journal	Journal of Clinical Investigation
Volume	130
Issue number	3
DOIs	https://doi.org/10.1172/JCI131145
State	Published - 2 Mar 2020
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by research grants from the Natural Sciences and Engineering Research Council of Canada (to XJY), Canadian Institutes of Health Research (CIHR, to XJY and PMC), Cancer Research Society (to XJY), and National Institutes of Health (CA129537 and GM109768, to TKP). This study makes use of DECIPHER (http://decipher.sanger.ac.uk), which is funded by Wellcome Trust. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003); see ref. 78 or www.ddduk.org/access. html for full acknowledgment. LL received stipend support from China Scholarship Council, the Clifford C.F. Wong Fellowship program, a CIHR/FRSQ training grant in cancer research for the McGill Integrated Cancer Research Training Program, and the Canderel Foundation.

Publisher Copyright:
© 2020, American Society for Clinical Investigation.

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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. M., Waisfisz, Q., Welner, S., Kingston, H., Hills, J. A., Boon, E. M. J., Basel-Salmon, L., Konen, O., Goldberg-Stern, H., Bazak, L., Tzur, S., ... Yang, X. J. (2020). Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability. Journal of Clinical Investigation, 130(3), 1431-1445. https://doi.org/10.1172/JCI131145

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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 influence 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 9 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 2 of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies 9 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 M.M.} and Quinten Waisfisz and Sara Welner and Helen Kingston and Hills, {Jordan A.} and Boon, {Elles M.J.} 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 Yang, {Xiang Jiao}",

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doi = "10.1172/JCI131145",

language = "אנגלית",

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Li, L, Ghorbani, M, Weisz-Hubshman, M, Rousseau, J, Thiffault, I, Schnur, RE, Breen, C, Oegema, R, Weiss, MMM, Waisfisz, Q, Welner, S, Kingston, H, Hills, JA, Boon, EMJ, 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, XJ 2020, 'Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability', Journal of Clinical Investigation, vol. 130, no. 3, pp. 1431-1445. https://doi.org/10.1172/JCI131145

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 M.M.

AU - Waisfisz, Quinten

AU - Welner, Sara

AU - Kingston, Helen

AU - Hills, Jordan A.

AU - Boon, Elles M.J.

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 - 2020/3/2

Y1 - 2020/3/2

N2 - Epigenetic integrity is critical for many eukaryotic cellular processes. An important question is how different epigenetic regulators control development and influence 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 9 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 2 of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies 9 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 influence 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 9 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 2 of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies 9 individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy, and other developmental anomalies.

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

Abstract

Bibliographical note

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