Iakoucheva Lab

University of California - San Diego, Department of Psychiatry

Research focus

The laboratory is involved in investigating molecular basis of psychiatric diseases using systems biology approaches. The goal is to discover pathways that connect genes carrying mutations identified in the exome and whole genome sequencing studies of autism and schizophrenia patients. We are building comprehensive co-expression and protein-protein interaction networks for autism and schizophrenia candidate genes and their alternatively spliced isoforms. We have built a network of interactions of over 400 brain-expressed isoforms of autism candidate genes (Nature Communications, 2014), thereby taking the autism interactome to an entirely new and more detailed level of understanding. We are also integrating brain RNA-seq data with our experimentally-derived networks to investigate how CNV and other protein-damaging mutations perturb such networks and pathways. We believe that tissue-specific networks of alternatively spliced isoforms are crucially important for improving our understanding of the mechanisms leading to psychiatric diseases. Using brain-specific spatio-temporal networks, we have identified an important pathway that is likely dysregulated by the 16p11.2 copy number changes and by autism mutations in the Cul3 ubiquitin ligase (Neuron, 2015). We found that the changes in RhoA levels might be an important factor determining microcephalic and macrocephalic phenotypes observed in the autism patients carrying these mutations. We are following up this pathway with transcriptomic and proteomic experiments in patients' fibroblast-derived and CRISPR-altered iPSC as well as the mouse model studies. Another interest of the laboratory are de novo non-coding mutations identified from the whole genome sequencing studies of autism families. We are developing computational algorithms to predict functional impact of both, coding and non-coding mutations using high-throughput genomic datasets. The long-term goal is to identify the pathways disrupted by the genetic mutations in autism and schizophrenia, and to target these pathways therapeutically.

CRISPR Mouse models of autism

The progress in identifying genetic causes of autism and other neurodevelopmental disorders has opened new possibilities for improving our understanding of the molecular mechanisms underlying these diseases. However, the knowledge of the molecular pathways that are disrupted by genetic mutations, and of those that could be targeted therapeutically, remains quite limited. Mouse models that carry human genetic mutations serve as important tools for improving the knowledge about these pathways. Utilizing the advanced genome engineering technology such as CRISPR-Cas9, we have generated various mouse models carrying mutations in the essential autism candidate genes, including the genes within the 16p11.2 copy number variant (CNV) chromosomal region, as well as the genes with other de-novo mutations. We are investigating the impact of these mutations at the cellular, transcriptional and translational levels using developing mouse brain. Our goal is to unravel detailed cellular and molecular mechanisms responsible for the disease phenotypes

Stem cell and cerebral organoid models of autism

The 16p11.2 copy number variant is associated with several neurodevelopmental disorders including autism and schizophrenia. There is a documented dosage effect of this CNV on the head size phenotype, with macrocephaly observed in the deletion carriers, and microcephaly observed with the duplication carriers. These human phenotypes have also been recapitulated in the animal models. Despite the accumulating evidence for the pathological effects of this CNV, the molecular mechanisms disrupted by it are still poorly understood. Our goal is to generate neurons and brain cerebral organoids from the skin cells of the patient carriers of these CNVs. The organoid models recapitulate brain development in a dish, and serve as excellent models for future studies of neurodevelopmental disorders. We are analyzing the transcriptomes and proteomes of these models by generating gene co-expression and protein-protein interaction networks to better characterize the pathways disrupted in these patients. We are also investigating the size and cellular composition of the cerebral organoids to capture different cell populations at different times of maturation.

Investigating the impact of autism mutations on brain isoform networks

Large-scale genomics studies have linked a number of genetic variants to autism. However, the underlying mechanism by which these variants lead to autism is still largely unknown. By taking into account of the intricate interactions among genes, the network biology approach provides a promising way to study how genetic variants contribute to etiology of autism. Traditional network analysis mainly focused on gene-level interactions, but each gene can produce a multitude of splicing variants or isoforms. Furthermore, different isoform may be expressed in different tissues or at different developmental periods, and thus exert unique biological functions. Our goal is to examine the relationships between splicing isoforms expression in the brain and de novo mutations identified in the patients with neurodevelopmental disorders. We are constructing a comprehensive spatiotemporal isoform transcriptome of the human brain, and mapping de novo mutations on these isoform networks. This would provide a more detailed resolution to the networks operating in the human brain.