Research in our lab
Identification of Disease-Associated Human RNA Pathways
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Our lab identifies and characterizes components of human RNA pathways implicated in devastating genetic diseases and cancers. To enable rapid and sensitive forward genetic identification of these pathways, we have developed novel approaches such as Fireworks, Mirror, and iterative screening of genome-wide guide RNA omission libraries.
These approaches have enabled us to identify novel components of human pathways acting on long non-coding RNA MALAT1 (Nature Communications, 2025 https://doi.org/10.1038/s41467-025-59998-3), two novel components of human nuclear RNase MRP (Cell Reports, 2025 https://doi.org/10.1016/j.celrep.2025.115752), and the RNase MRP and RNase P control (RMPPc) pathway that regulates non-canonical 3′-end processing of lncRNAs MALAT1 and MEN-β, post-transcriptional processing of internal transcribed spacers in pre-rRNA and 5′-leader sequences in pre-tRNA (Panah et al., 2025, under review). |
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We are specifically interested in:
– Forward genetic identification of the pathways of nuclear biogenesis, regulation, and surveillance of human long non-coding RNAs (lncRNAs), exemplified by cancer-associated nuclear lncRNA MALAT1. Our forward genetic screening in human cells identified complexes required for MALAT1 3′ end nuclear surveillance, components required for nuclear MALAT1 mascRNA maturation, and numerous additional candidate genes that require further investigation. Previously, such nuclear lncRNA pathways have been completely refractory to forward genetics.
– Discovery of factors in human mRNA surveillance. Our previous work identified multiple known nonsense-mediated mRNA degradation components as well as candidate genes, providing an experimental platform for discovery of additional targets for potential enhancement of nonsense suppression therapies of human genetic disorders.
– Development of technology for massive shotgun mutational interrogation of the entire human genome. Unlike traditional knockdowns and knockouts, the approach is intended to interrogate coding, non-coding, and intergenic genomic regions. The method provides an unbiased tool for mutational analysis of the diploid human genome and aims to pinpoint critical residues within multi-functional and essential gene products that could be targeted to inhibit disease-associated human pathways with minimal toxicity.
– Genome-scale identification of redundantly acting human gene pairs. Unbiased genome-scale experimental identification of redundantly acting human genes is currently impossible due to prohibitively large number of pairwise gene combinations. The ultra-high throughput screening technology employed by our lab provides an experimental platform for genome-scale forward genetic discovery of pairwise therapeutic targets within disease-associated human pathways.
– Forward genetic identification of the pathways of nuclear biogenesis, regulation, and surveillance of human long non-coding RNAs (lncRNAs), exemplified by cancer-associated nuclear lncRNA MALAT1. Our forward genetic screening in human cells identified complexes required for MALAT1 3′ end nuclear surveillance, components required for nuclear MALAT1 mascRNA maturation, and numerous additional candidate genes that require further investigation. Previously, such nuclear lncRNA pathways have been completely refractory to forward genetics.
– Discovery of factors in human mRNA surveillance. Our previous work identified multiple known nonsense-mediated mRNA degradation components as well as candidate genes, providing an experimental platform for discovery of additional targets for potential enhancement of nonsense suppression therapies of human genetic disorders.
– Development of technology for massive shotgun mutational interrogation of the entire human genome. Unlike traditional knockdowns and knockouts, the approach is intended to interrogate coding, non-coding, and intergenic genomic regions. The method provides an unbiased tool for mutational analysis of the diploid human genome and aims to pinpoint critical residues within multi-functional and essential gene products that could be targeted to inhibit disease-associated human pathways with minimal toxicity.
– Genome-scale identification of redundantly acting human gene pairs. Unbiased genome-scale experimental identification of redundantly acting human genes is currently impossible due to prohibitively large number of pairwise gene combinations. The ultra-high throughput screening technology employed by our lab provides an experimental platform for genome-scale forward genetic discovery of pairwise therapeutic targets within disease-associated human pathways.
Please, feel free to stop by in our lab (rooms 134-135) in the Institute for Human Genetics or email Andrei Alexandrov ([email protected]) to learn more about our research projects.
