Functional Genomics

Autism spectrum disorders (ASD) were thought to be disorders of the synapse due to the burden of mutations in synaptic genes, however recent publications (Talkowski et al., Cell 2012) have pointed in a new direction, showing a great number of high risk chromatin-related genes. Indeed, chromatin regulators are essential for brain development as they control neurogenesis and neural differentiation and rely on epigenetic marks as post-translational modifications of histones.
In a recent study, we have sought to define the changes in patterns of chromatin modification and RNA expression of strong effect ASD genes, as CHD8. We suppressed CHD8 in iPS-derived neural precursor cells and integrated RNAseq with ChIPseq data to identify widespread changes in gene expression and pervasive chromatin binding of CHD8 throughout the genome. We identified pathways related to chromatin modification, transcriptional regulation, and synaptic transmission that were altered as a consequence of CHD8 loss-of-function, and found a strong enrichment of previously identified ASD genes among the genes and pathways that were regulated by CHD8. We also identified important expression changes associated with developmental timing in the brain.


Sugathan et al., 2014, PNAS

The 16p11.2 microdeletion/ microduplication syndrome is one of the most common recurrent CNVs ( ~1% of all ASD cases) and involves a 593 kb segment containing 30 genes, flanked by two segmental duplications of > 99% homology. A collaboration with colleagues at Duke University (Golzio and Katsanis) previously identified KCTD13 as a driver of neuroanatomical phenotypes observed within the region. We used a multi-faceted functional genomic approach to delineate the functional consequences of the loss or gain of this region and understand its functional impact genome-wide, using both in vivo and in vitro models of disease. We conducted RNAseq analysis of multiplex families harboring CNV and cortical tissue from mouse models with deletion and duplication of the syntenic 7qf3 region. We observed global effects of the CNV on the gene expression, with the strongest effects being consistently within the CNV region itself. We further observed cis positional effects telemetric to the CNV and in trans with genomic segments with physical interactions as evidenced by HI-C data. Computationally derived networks of genes with altered expression found association, in both the LCL and mouse brain, with multiple hypothesis of ASD pathogenesis. In a follow-up study, through collaboration with our colleagues in the 16p11.2 European consortium, we found strong overlap in gene expression signatures from a large cohort of patients with deletion and duplication of the CNV, as well as enrichment of genes involved in classic forms of intellectual disability such as ciliopathies. In ongoing studies, we are now evaluating tissue specific alterations associated with this CNV.


Golzio et al., 2012, Nature
Blumenthal et al., 2014, AJHG
Migliavacca et al., 2015, AJHG