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

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

Shohat, S., Vol, E. & Shifman, S. Gene essentiality in cancer cell lines is modified by the sex chromosomes. Genome Res (2022).Abstract
Human sex differences arise from gonadal hormones and sex chromosomes. Studying the direct effects of sex chromosomes in humans is still challenging. Here we studied how the sex chromosomes can modulate gene expression and the outcome of mutations across the genome by exploiting the tendency of cancer cell lines to lose or gain sex chromosomes. We inferred the dosage of the sex chromosomes in 355 female and 408 male cancer cell lines and used it to dissect the contribution of the Y and X Chromosomes to sex-biased gene expression. Furthermore, based on genome-wide CRISPR screens, we identified genes whose essentiality is different between male and female cells depending on the sex chromosomes. The most significant genes were X-linked genes compensated by Y-linked paralogs. Our sex-based analysis identifies genes that, when mutated, can affect male and female cells differently and reinforces the role of the X and Y-Chromosomes in sex-specific cell function.

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. EMBO Rep e54720 (2022).Abstract
Insulator proteins located at the boundaries of topological associated domains (TAD) are involved in higher-order chromatin organization and transcription regulation. However, it is still not clear how long-range contacts contribute to transcriptional regulation. 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 find that ROW physically interacts with heterochromatin proteins (HP1b and HP1c) and the insulator protein (BEAF-32). These proteins interact at TAD boundaries where ROW, through its AT-hook motifs, binds AT-rich sequences flanked by BEAF-32-binding sites and motifs. Knockdown of row downregulates genes that are long-range targets of BEAF-32 and bound indirectly by ROW (without binding motif). Analyses of high-throughput chromosome conformation capture (Hi-C) data reveal 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, including HP1 proteins, to regulate the transcription of developmental and inducible genes through long-range interactions.

Identification of genetic mechanisms for tissue-specific genetic effects based on CRISPR screens

Dvir, E., Shohat, S., Flint, J. & Shifman, S. Identification of genetic mechanisms for tissue-specific genetic effects based on CRISPR screens. Genetics (2022).Abstract
A major challenge in genetic studies of complex diseases is to determine how the action of risk genes is restricted to a tissue or cell type. Here we investigate tissue specificity of gene action using CRISPR screens from 786 cancer cell lines originating from 24 tissues. We find that the expression pattern of the gene across tissues explains only a minority of cases of tissue-specificity (9%), while gene amplification and the expression levels of paralogs account for 39.5% and 15.5%, respectively. Additionally, the transfer of small molecules to mutant cells explains tissue-specific gene action in blood. The tissue-specific genes we found are not specific just for human cancer cell lines: we found that the tissue-specific genes are intolerant to functional mutations in the human population and are associated with human diseases more than genes that are essential across all cell types. Our findings offer important insights into genetic mechanisms for tissue specificity of human diseases.

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.
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