Mutation of the CH1 Domain in the Histone Acetyltransferase CREBBP Results in Autism-Relevant Behaviors in Mice

PLOS ONE, Dec 2019

Autism spectrum disorders (ASDs) are a group of neurodevelopmental afflictions characterized by repetitive behaviors, deficits in social interaction, and impaired communication skills. For most ASD patients, the underlying causes are unknown. Genetic mutations have been identified in about 25 percent of ASD cases, including mutations in epigenetic regulators, suggesting that dysregulated chromatin or DNA function is a critical component of ASD. Mutations in the histone acetyltransferase CREB binding protein (CBP, CREBBP) cause Rubinstein-Taybi Syndrome (RTS), a developmental disorder that includes ASD-like symptoms. Recently, genomic studies involving large numbers of ASD patient families have theoretically modeled CBP and its paralog p300 (EP300) as critical hubs in ASD-associated protein and gene interaction networks, and have identified de novo missense mutations in highly conserved residues of the CBP acetyltransferase and CH1 domains. Here we provide animal model evidence that supports this notion that CBP and its CH1 domain are relevant to autism. We show that mice with a deletion mutation in the CBP CH1 (TAZ1) domain (CBPΔCH1/ΔCH1) have an RTS-like phenotype that includes ASD-relevant repetitive behaviors, hyperactivity, social interaction deficits, motor dysfunction, impaired recognition memory, and abnormal synaptic plasticity. Our results therefore indicate that loss of CBP CH1 domain function contributes to RTS, and possibly ASD, and that this domain plays an essential role in normal motor function, cognition and social behavior. Although the key physiological functions affected by ASD-associated mutation of epigenetic regulators have been enigmatic, our findings are consistent with theoretical models involving CBP and p300 in ASD, and with a causative role for recently described ASD-associated CBP mutations.

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Mutation of the CH1 Domain in the Histone Acetyltransferase CREBBP Results in Autism-Relevant Behaviors in Mice

January Mutation of the CH1 Domain in the Histone Acetyltransferase CREBBP Results in Autism- Relevant Behaviors in Mice Fei Zheng 0 1 2 Lawryn H. Kasper 0 1 2 David C. Bedford 0 1 2 Stephanie Lerach 0 1 2 Brett J. W. Teubner 0 1 2 Paul K. Brindle 0 1 2 0 1 Department of Biochemistry, St Jude Children's Research Hospital , Memphis, TN 38105 , United States of America, 2 Department of Developmental Neurobiology, St Jude Children's Research Hospital , Memphis, TN 38105 , United States of America 1 Funding: This work was supported by NIH grants R21 DE018183 (P.B.) , R01 DC012833, R01 MH097742 and R01 MH095810 (S.Z.) , Cancer Center (CORE) support grant P30 CA021765, and the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript 2 Editor: Nicoletta Landsberger, University of Insubria , ITALY Autism spectrum disorders (ASDs) are a group of neurodevelopmental afflictions characterized by repetitive behaviors, deficits in social interaction, and impaired communication skills. For most ASD patients, the underlying causes are unknown. Genetic mutations have been identified in about 25 percent of ASD cases, including mutations in epigenetic regulators, suggesting that dysregulated chromatin or DNA function is a critical component of ASD. Mutations in the histone acetyltransferase CREB binding protein (CBP, CREBBP) cause Rubinstein-Taybi Syndrome (RTS), a developmental disorder that includes ASD-like symptoms. Recently, genomic studies involving large numbers of ASD patient families have theoretically modeled CBP and its paralog p300 (EP300) as critical hubs in ASD-associated protein and gene interaction networks, and have identified de novo missense mutations in highly conserved residues of the CBP acetyltransferase and CH1 domains. Here we provide animal model evidence that supports this notion that CBP and its CH1 domain are relevant to autism. We show that mice with a deletion mutation in the CBP CH1 (TAZ1) domain (CBPΔCH1/ΔCH1) have an RTS-like phenotype that includes ASD-relevant repetitive behaviors, hyperactivity, social interaction deficits, motor dysfunction, impaired recognition memory, and abnormal synaptic plasticity. Our results therefore indicate that loss of CBP CH1 domain function contributes to RTS, and possibly ASD, and that this domain plays an essential role in normal motor function, cognition and social behavior. Although the key physiological functions affected by ASD-associated mutation of epigenetic regulators have been enigmatic, our findings are consistent with theoretical models involving CBP and p300 in ASD, and with a causative role for recently described ASD-associated CBP mutations. - OPEN ACCESS Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Introduction Autism spectrum disorders (ASDs) are distinguished by repetitive behaviors, deficits in social interaction, and impaired communication skills [ 1–4 ]. The genetics of these disorders are often Competing Interests: The authors have declared that no competing interests exist. complex and the cause of ASD is unknown for many patients. Single-gene syndromes account for only 7–9% of ASDs with heterogeneneous comorbidities including hyperactivity, intellectual disability, and other neurological symptoms [ 4,5 ]. Many of the ASD associated mutations that have been found occur in genes that encode epigenetic and chromatin regulators, suggesting that aberrant chromatin or DNA function contributes to ASD [ 6 ]. Although more than 667 ASD candidate genes have been defined so far (Source: SFARI Gene 2.0, [ 7 ]), only a limited number of ASD mouse models have been developed. Therefore, mouse models with mutations in ASD syndromic genes are valuable for studying the converging mechanisms for ASDs that arise from mutations in different genes with biologically related roles. CBP (CREBBP, CREB binding protein) and its paralog p300 (EP300) comprise the KAT3 family of histone acetyltransferases (HATs) [ 8 ], and mainly function as transcriptional co-activators [ 9 ]. CBP has one histone acetyltransferase domain (HAT domain) and several proteinbinding domains including KIX, CH1 and CH3, the latter of which are principally modeled to recruit CBP to DNA-bound transcription factors (S1 Fig). We have previously described knock-in mice having an in-frame 52 amino acid deletion within the highly conserved 88 residue CBP CH1 domain [ 10 ]. This deletion removes amino acids 342–393, which includes the first two of four alpha helices in the CH1 domain and five of its twelve zinc-chelating residues, thereby disrupting the domain structure and ability to bind transcriptional regulators (e.g. HIF and CITED2) without affecting CBP expression level or acetyltransferase activity [ 10–13 ]. Heterozygous mutations in CREBBP and, to (...truncated)


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Fei Zheng, Lawryn H. Kasper, David C. Bedford, Stephanie Lerach, Brett J. W. Teubner, Paul K. Brindle. Mutation of the CH1 Domain in the Histone Acetyltransferase CREBBP Results in Autism-Relevant Behaviors in Mice, PLOS ONE, 2016, Volume 11, Issue 1, DOI: 10.1371/journal.pone.0146366