Assistant Professor, Department of Genetics and Biochemistry
Before joining the Clemson Center for Human Genetics, Dr. Alexandrov was a scientist at Yale University where he studied disease-associated human RNA pathways funded by the National Institute of Neurological Disorder and Stroke and the National Human Genome Research Institute. Dr. Alexandrov received his PhD at the University of Rochester School of Medicine and had his post-doctoral training in the (i) Center for Human Genetics and Molecular Pediatric Disease at the University of Rochester and (ii) Department of Molecular Biochemistry and Biophysics at Yale University. In the lab of Dr. Eric Phizicky in Rochester, Dr. Alexandrov used genetic interaction screening and identified a novel RNA surveillance pathway he named the Rapid tRNA Degradation (RTD) pathway. Subsequently, in the lab of Dr. Joan Steitz at Yale, Dr. Alexandrov developed an ultra-high throughput method that enables forward genetic discovery of genes involved in human RNA surveillance. He applied this approach to identify components of the human nonsense-mediated mRNA degradation (NMD) pathway and is currently using this technology to identify components responsible for biogenesis, regulation, and surveillance of disease-associated human nuclear long non-coding RNAs.
The lab of Dr. Alexandrov uses forward genetics and ultra-high throughput CRISPR-based genome interrogation to identify components of disease-associated human RNA pathways. The lab extensively employs fluorescence-activated cell sorting (FACS), complex CRISPR guide RNA libraries, and in vivo fluorescence amplification to expand opportunities provided by forward genetics in human cells. The lab’s goal is to identify and tackle components of RNA pathways implicated in devastating human genetic diseases and cancers. Specifically, Dr. Alexandrov lab is 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. Dr. Alexandrov’s forward genetic screening identified complexes required for MALAT1 3′ end nuclear surveillance, components required for nuclear MALAT1 mascRNA maturation, and additional candidate genes. 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 Alexandrov’s lab provides an experimental platform for genome-scale forward genetic discovery of pairwise therapeutic targets within disease-associated human pathways.
Alexandrov A., Shu M.D., Steitz J.A. (2017) Fluorescence Amplification Method for Forward Genetic Discovery of Factors in Human mRNA Degradation. Molecular Cell. 65(1):191-201. PMC5301997.
Herbert K.M., Pimienta G., DeGregorio S.J., Alexandrov A., Steitz J.A. (2013) Phosphorylation of DGCR8 increases its intracellular stability and induces a progrowth miRNA profile. Cell Reports. 2013; 5(4):1070-81. PMID: 24239349.