The Peixoto lab
Autism spectrum disorder (ASD) is the most prevalent neurodevelopmental disorder in the US. Recent estimates from the Centers for Disease Control and Prevention (CDC) show that 1 in 68 children are currently diagnosed with ASD. ASD affects all areas of child development and often co-occurs with other disorders or associated problems. There is a wide range of severity within ASD and increased severity translates to increased caregiver burden. Severity is often defined relative to the ability of an individual to function but it is hard to measure and quantify. Co-occurring disorders such as Intellectual disability (ID) and sleep impairments increase severity within ASD. The research in the lab focuses on defining and understanding factors that impact ASD severity. We are interested in genetic risk factors and mechanisms underlying the presence of co-occurring problems that increase ASD severity, such as ID and poor sleep.
ASD and Sleep
Several studies have demonstrated that sleep problems occur in ASD at a much higher rate than in typical development, affecting 40-80% of this population. These problems include significant delays in sleep onset, multiple night awakenings and overall less sleep. Sleep problems are a good predictor of severity of core ASD diagnostic symptoms, such as communication deficits and repetitive behaviors. Despite a rapidly growing number of studies documenting sleep problems in ASD, little is known about its exact nature and underlying mechanisms. To advance the study of sleep in ASD, we decided to focus on Shank3, a high confidence gene candidate linked to ASD. Shank3 is a synaptic scaffolding protein for which mutations have been found to be associated with a substantially increased risk for ASD. In humans, complete deletion of Shank3 leads to Phelan McDermid syndrome (PMS), a rare disease strongly associated with ASD. A K01 career development award from the NIH/NINDS was funded to carry out research to understand the mechanisms underlying sleep impairments using Shank3 mutant mice. We teamed up with PMS foundation to show that PMS patients have significant problems falling and staying asleep. Our research shows that Shank3 mutant mice have difficulty falling asleep.
To be able to interpret differences in genome-wide gene expression in mutants it is essential we understand the molecular underpinnings of normal sleep. During postdoctoral research Dr. Peixoto used genome-wide gene expression analysis to show that sleep deprivation causes massive changes in gene expression in the hippocampus of mice that have the functional consequence of repressing translation. We have extended those studies to define molecular signatures of sleep regulation in the cortex Gerstner et al. BMC Genomics 2016. We are currently using RNA-seq study of gene expression following sleep deprivation in the pre-frontal cortex to characterize the impact of sleep deprivation in alternative splicing. Two R21 NINDS and NICHD funded grants in collaboration with the laboratory of Dr. Marcos Frank support the study of other aspects of the molecular function of sleep using genomic approaches.
Our research in now available in elife:
ASD and Learning
Intellectual Disability (ID) is the most common ASD comorbidity, and leads to learning impairments that are the strongest predictor of poor prognosis and lifetime cost of treatment. The genetic basis and underlying molecular mechanisms shared between learning and ASD therefore hold insights into a key aspect of these disorders. Learning is known to require regulation of gene expression and epigenetic modifications. We hypothesized that the connection between ASD and ID must be determined at least in part by epigenetic modifications and the regulatory regions they target – providing an unexplored and potentially fruitful target for investigation. We conducted experiments characterizing the effects of learning in chromatin accessibility genome-wide in the hippocampus of wild-type mice. We then developed DEScan, an R language bioinformatics strategy that enables the analysis of data from epigenomic experiments containing multiple replicates. DEScan revealed changes in chromatin accessibility at 2365 regulatory regions—most of which were promoters. Learning-regulated promoters were active during forebrain development in mice and were enriched in epigenetic modifications indicative of bivalent promoters. These promoters were disproportionally intronic, showed a complex relationship with gene expression and alternative splicing during memory consolidation and retrieval, and were enriched in the data set relative to known ASD risk genes. Genotyping in the clinical cohort within one of these promoters (SHANK3 promoter 6) revealed that the SNP rs6010065 was associated with ASD. Our data support the idea that learning recapitulates development at the epigenetic level and demonstrate that behaviorally induced epigenetic changes in mice can highlight regulatory regions relevant to brain disorders in patients. This research was published as the Cover of Science Signaling in January 2018.
The goal of the Peixoto lab is to focus on factors that substantially affect the quality of life of affected individuals and their families. Understanding the molecular mechanisms underlying sleep and cognitive impairments in ASD will provide novel insights on the two factors that have the greatest impact on ASD severity. In the long-term our studies will pave the way for new therapies and treatments targeted to improve quality of life for those at the more severe end of the Autism Spectrum, who currently have the poorest prognosis and the highest lifetime cost of treatment.