CBP Histone Acetyltransferase Activity Regulates Embryonic Neural Differentiation in the Normal and Rubinstein-Taybi Syndrome Brain

• Published in: Developmental cell 2010-01, Vol.18 (1), p.114-125
• Main Authors: Wang, Jing, Weaver, Ian C.G., Gauthier-Fisher, Andrée, Wang, Haoran, He, Ling, Yeomans, John, Wondisford, Frederic, Kaplan, David R., Miller, Freda D.
• Format: Article
• Language: English
• Subjects: Acetylation; Animals; Biological and medical sciences; Brain - abnormalities; Brain - enzymology; Brain - physiopathology; Cell Differentiation - genetics; Cell differentiation, maturation, development, hematopoiesis; Cell Lineage - genetics; Cell physiology; Cells, Cultured; CREB-Binding Protein - genetics; CREB-Binding Protein - metabolism; DEVBIO; Diseases of the osteoarticular system; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental - physiology; Histones - genetics; Histones - metabolism; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Mental Disorders - enzymology; Mental Disorders - genetics; Mental Disorders - physiopathology; Mice; Mice, Knockout; Mice, Transgenic; Molecular and cellular biology; MOLNEURO; Nervous System Malformations - enzymology; Nervous System Malformations - genetics; Nervous System Malformations - physiopathology; Neurogenesis - physiology; Promoter Regions, Genetic - genetics; Protein Kinase C - genetics; Protein Kinase C - metabolism; RNA Interference; Rubinstein-Taybi Syndrome - enzymology; Rubinstein-Taybi Syndrome - genetics; Rubinstein-Taybi Syndrome - physiopathology; Stem Cells - enzymology
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2009.10.023

Increasing evidence indicates that epigenetic changes regulate cell genesis. Here, we ask about neural precursors, focusing on CREB binding protein (CBP), a histone acetyltransferase that, when haploinsufficient, causes Rubinstein-Taybi syndrome (RTS), a genetic disorder with cognitive dysfunction. We show that neonatal cbp+/− mice are behaviorally impaired, displaying perturbed vocalization behavior. cbp haploinsufficiency or genetic knockdown with siRNAs inhibited differentiation of embryonic cortical precursors into all three neural lineages, coincident with decreased CBP binding and histone acetylation at promoters of neuronal and glial genes. Inhibition of histone deacetylation rescued these deficits. Moreover, CBP phosphorylation by atypical protein kinase C ζ was necessary for histone acetylation at neural gene promoters and appropriate differentiation. These data support a model in which environmental cues regulate CBP activity and histone acetylation to control neural precursor competency to differentiate, and indicate that cbp haploinsufficiency disrupts this mechanism, thereby likely causing cognitive dysfunction in RTS. ► CBP+/− mice show early cognitive dysfunction, like Rubinstein-Taybi syndrome (RTS) ► CBP promotes neurogenesis by enhancing histone acetylation at neural promoters ► Atypical PKC phosphorylates CBP to regulate histone acetylation