Welcome to the Neurogenetics Lab

the lab

Genetics of Neurodevelopmental Disorders

Our research group aims to identify and characterize genes involved in human neurodevelopmental and psychiatric disorders as a first step towards understanding the mechanism of disease. Our studies are focused on the genetics of autism and schizophrenia. We are using a combination of genetic and functional genomics methods to identify new genes and molecular pathways that contribute to those disorders. We also study the influence of genetic variations on gene expression as a way to understand how genetic variations may lead to neurodevelopmental disorders.

Recent Publications

Genetic mechanisms for tissue-specific essential genes.

Dvir, E., Shohat, S. & Shifman, S. Genetic mechanisms for tissue-specific essential genes. bioRxiv (Submitted). Publisher's VersionAbstract
Genetic diseases often manifest in specific tissues despite having the genetic risk variants in all cells. The most commonly assumed mechanism is selective expression of the causal gene in the pathogenic tissues, but other mechanisms are less explored. Using CRISPR screens from 789 cell lines and 27 lineages, we identified 1274 lineage-specific essential genes (LSEGs). We show that only a minority of LSEGs are explained by preferential expression (n = 115), and a big proportion of them (n = 509) is explained by lineage-specific gene amplification. Three other mechanisms were identified by genome-wide expression analysis. First, lineage-specific expression of paralogs leads to reduced functional redundancy and can account for 153 LSEGs. Second, for 45 LSEGs, the paralog expression increases vulnerability, implying functional codependency. Third, we suggest that the transfer of small molecules to mutant cells could explain blood-specific essentiality. Overall, LSEGs were more likely to be associated with human diseases than common essential genes, were highly intolerant to mutations and function in developmental pathways. Analysis of diverse human cell types found that the expression specificity of LSEGs and their paralogs is consistent with preferential expression and functional redundancy being a general phenomenon. Our findings offer important insights into genetic mechanisms for tissue specificity of human diseases.

The chromatin factor ROW cooperates with BEAF-32 in regulating long-range inducible genes

Herman, N., Kadener, S. & Shifman, S. The chromatin factor ROW cooperates with BEAF-32 in regulating long-range inducible genes. bioRxiv (Submitted). Publisher's VersionAbstract
Insulator proteins located at the boundaries of topological associated domains (TAD) are involved in regulating chromatin loops. Yet, how chromatin loops contribute to transcription regulation is still not clear. Here we show that Relative-of-WOC (ROW) is essential for the long-range transcription regulation mediated by the Boundary Element-Associated Factor of 32kD (BEAF-32). We found that ROW physically interacts with heterochromatin proteins (HP1b and HP1c) and the insulator protein BEAF-32. The co-localization happens at TAD boundaries where ROW, through its AT-hooks motifs, binds AT-rich sequences flanked by BEAF-32 binding sites and motifs. Knockdown of row resulted in downregulation of genes that are long-range targets of BEAF-32 and bound indirectly by ROW (without binding motif). Analysis of high- throughput chromosome conformation capture (Hi-C) data revealed long-range interactions between promoters of housekeeping genes bound directly by ROW and promoters of developmental genes bound indirectly by ROW. Thus, our results show cooperation between BEAF-32 and the ROW complex, which includes HP1 proteins, to regulate the transcription of developmental and inducible genes by chromatin loops.

Gene essentiality in cancer cell lines is modified by the sex chromosomes

Shohat, S. & Shifman, S. Gene essentiality in cancer cell lines is modified by the sex chromosomes. bioRxiv (Submitted). Publisher's VersionAbstract
Human sex differences are thought to arise from gonadal hormones and genes on the sex chromosomes. Here we studied how sex and the sex chromosomes can modulate the outcome of mutations across the genome. We used the results of genome-wide CRISPR-based screens on 306 female and 396 male cancer cell lines to detect differences in gene essentiality between the sexes. By exploiting the tendency of cancer cells to lose or gain sex chromosomes, we were able to dissect the contribution of the Y and X chromosomes to variable gene essentiality. Using this approach, we identified 178 differentially essential genes that depend on the biological sex or the sex chromosomes. Integration with sex bias in gene expression and the rate of somatic mutations in human tumors highlighted genes that escape from X-inactivation, cancer-testis antigens, and Y-linked paralogs as central to the functional genetic differences between males and females.

Transfer RNA fragments replace microRNA regulators of the cholinergic poststroke immune blockade

Winek, K., et al. Transfer RNA fragments replace microRNA regulators of the cholinergic poststroke immune blockade. Proc Natl Acad Sci U S A (2020).Abstract
Stroke is a leading cause of death and disability. Recovery depends on a delicate balance between inflammatory responses and immune suppression, tipping the scale between brain protection and susceptibility to infection. Peripheral cholinergic blockade of immune reactions fine-tunes this immune response, but its molecular regulators are unknown. Here, we report a regulatory shift in small RNA types in patient blood sequenced 2 d after ischemic stroke, comprising massive decreases of microRNA levels and concomitant increases of transfer RNA fragments (tRFs) targeting cholinergic transcripts. Electrophoresis-based size-selection followed by qRT-PCR validated the top six up-regulated tRFs in a separate cohort of stroke patients, and independent datasets of small and long RNA sequencing pinpointed immune cell subsets pivotal to these responses, implicating CD14 monocytes in the cholinergic inflammatory reflex. In-depth small RNA targeting analyses revealed the most-perturbed pathways following stroke and implied a structural dichotomy between microRNA and tRF target sets. Furthermore, lipopolysaccharide stimulation of murine RAW 264.7 cells and human CD14 monocytes up-regulated the top six stroke-perturbed tRFs, and overexpression of stroke-inducible tRF-22-WE8SPOX52 using a single-stranded RNA mimic induced down-regulation of immune regulator Z-DNA binding protein 1. In summary, we identified a "changing of the guards" between small RNA types that may systemically affect homeostasis in poststroke immune responses, and pinpointed multiple affected pathways, which opens new venues for establishing therapeutics and biomarkers at the protein and RNA level.
Google Scholar