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
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
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Research Article Neuroscience

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.

Authors

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

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Figure 1

Conditional Kat8 deletion causes early lethality and cerebral hypoplasia.

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Conditional Kat8 deletion causes early lethality and cerebral hypoplasia...
(A) Growth curves for control and homozygous knockout (cKO) mice (n = 14 and 4, respectively). (B) Photos of wild-type and cKO mice at P21. (C) Enlarged photos of head parts of the mice shown in B. The “flat-head” phenotype refers to the flat head surface above the cerebrum (indicated with a red arrowhead). (D) Photos of deskinned heads from the mice shown in B. (E) Brain images for the wild-type and cKO mice shown in B. (F) Representative brain images for the wild-type and cKO mice at P5. See Supplemental Figure 2, C–F, for brain images of another pair at P5 and 3 pairs at P1, E18.5, and E16.5. (G) Brain weight at P1, P5, and P22 (n = 5, 3, and 4 for each genotype, respectively). (H and I) Nissl staining of sagittal (H) or coronal (I) brain sections at P22 or P6. (J–L) Nissl staining of coronal (J) or sagittal (K–L) embryo sections at E16.5, E13.5, or E12.5. For panels H–L, mainly the cerebrum or its precursor is shown. Dashed lines demarcate the cerebral cortex. The mutant cortex is largely lost at P6 (I) and P22 (H). Neocortical and hippocampal lamination is not evident in the mutant at E16.5 (J). The small mutant LGE at E12.5 is due to section orientation. For (B–F), images are representative of 5 pairs of wild-type and mutant mice, and for (H–L), each image is representative of 3 experiments. For A and G, unpaired 2-tailed Student’s t tests were used; ***P < 0.001. Scale bars: 2 mm (E), 1 mm (F and H–J), and 0.5 mm (K–L). Cb, cerebellum; CP, cortical plate; Cx, cerebral cortex; Hp, hippocampus; Hp-Pri, hippocampal primordium; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; Ob, olfactory bulb; Th, thalamus.