CBP histone acetyltransferase activity regulates embryonic neural differentiation in the normal and Rubinstein-Taybi syndrome brain.
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 zeta 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.
Developmental and Stem Cell Biology Program, Hospital for Sick Children, 555 University Ave., Toronto, ON, Canada.
Jing
J
Wang
Ian C G
IC
Weaver
Andrée
A
Gauthier-Fisher
Haoran
H
Wang
Ling
L
He
John
J
Yeomans
Frederic
F
Wondisford
David R
DR
Kaplan
Freda D
FD
Miller
D000107:Acetylation; D000818:Animals; D001921:Brain / Q000002:abnormalities* / Q000201:enzymology* / Q000503:physiopathology; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D001523:Mental Disorders / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009421:Nervous System Malformations / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D055495:Neurogenesis / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012415:Rubinstein-Taybi Syndrome / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D013234:Stem Cells / Q000201:enzymology
D004268:DNA-Binding Proteins; D006657:Histones; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; C115015:PKC-3 protein; D011493:Protein Kinase C