Career
Singh began his academic career as a Postdoctoral Research Associate,holding an appointment initially at the University of Texas MD Anderson Cancer Center,then at Oregon State University,and later at the University of Texas at Austin. In 2001,he became a Special and Scientific Staff and Research Assistant Professor at the New England Medical Center and Tufts University School of Medicine,followed by an appointment as assistant professor in the Department of Medicine at the University of Massachusetts,where he worked on the development of the ISS-N1 until 2007. [6] He joined Iowa State University as an associate professor in 2007 and was named the Salsbury Endowed Chair in Veterinary Medicine from 2008 to 2016. Since 2012,he has been serving as a professor in the Department of Biomedical Sciences of the College of Veterinary Medicine at Iowa State University, [1] where he leads the Singh research group. He is also affiliated with the Roy J. Carver Department of Biochemistry,Biophysics and Molecular Biology at Iowa State University,where he served as the member of the Biotechnology Council and Graduate Council. [7] [8] [9]
Research
As an independent investigator,Singh has contributed to the field of molecular biology by studying the mechanism of alternative splicing,particularly in the context of spinal muscular atrophy (SMA),and developing targeted therapies,including antisense drugs,for correcting aberrant splicing associated with genetic diseases. [2] His early research focused on purification and characterization of enzymes,including cellulases,transglutaminases,and RNA replicase from Turnip Yellow Mosaic Virus. Working in the laboratory of Alan Lambowitz,he also analyzed how the maturase LtrA binds to the Ll.LtrB Group II intron in Lactococcus lactis,facilitating cDNA synthesis and shedding light on its role in RNA splicing and its evolutionary origins. [10]
Singh delved into the functions of the Survival Motor Neuron (SMN) protein in RNA metabolism,linking its roles to SMA and various other conditions. [11] Collaborating with Nirmal K. Singh,Natalia N. Singh and Elliot J. Androphy,he investigated the function of the intronic splicing silencer N1 (ISS-N1) in the SMN2 gene,its involvement in exon 7 skipping and its therapeutic potential for SMA, [12] [13] leading to the first medical therapy for the condition [14] and earning patents. [15] [16] He also established that an 8-mer antisense oligonucleotide (ASO) corrects SMN2 exon 7 splicing aberrations in SMA models,increasing SMN levels with specificity and efficacy. [17] Furthermore,he examined the C6U mutation,and exonic splicing enhancers in exon 7 of the SMN gene,shedding light on the regulation of splicing in SMA. [18]
Singh explored how RNA structure,specifically terminal stem loop 2 (TSL2),influences exon 7 splicing in the SMN genes, [19] and identified TIA1 and TIAR proteins as positive regulators of SMN2 exon 7 splicing, [20] revealing insights into SMA pathology. He developed a multi-exon skipping detection assay (MESDA) to capture multiple splice isoforms of SMN genes in a single experiment. [21] He uncovered therapeutic significance of an RNA structure formed by a long-distance interaction within an intron, [22] and demonstrated how a small ASO (8-mer ASO) could be used for therapeutic splicing correction in SMA. [17] His research also revealed an association of male infertility with the low SMN levels in a mild mouse model of SMA, [23] and showed how activation of a cryptic splice site could be exploited for the treatment of rare cases of SMA. [24] In addition,he showcased novel sequence and structural motifs associated with RNA-SMN interactions, [25] and discovered a huge repertoire of circular RNAs (circRNAs) generated by human SMN genes. [26] In a paper published in Scientific Reports,he showed aberrant transcription of genes on chromosomes 4,7,10 and X upon overexpression of a circRNA encompassing four early exons of SMN genes. [27] His research identified and characterized off-target effects of splicing modulating therapeutic compounds,including ASOs and small molecules, [28] [29] with his laboratory being the first to construct the super minigene to examine the effect of genetic mutations on transcription,splicing and translation. [30]
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