Kiledjian Lab - Research

           DcpS Scavenger Decapping: We showed that the DcpS scavenger decapping enzyme, that functions in the 3´-end decay of RNA is essential for normal cognition. Individuals with a disruption of DcpS decapping activity exhibit cognitive and neurogenesis impairment (Ahmed et al., 2015). Using induced pluripotent stem cells (iPSCs) generated from individuals with homozygous disruption of the DCPS gene, we have shown both their differentiation into neurons and the generation of neurite outgrowth are compromised (Salamon et al., 2022). More recently we demonstrated that the DCPS disrupted cells harbor a metabolite defect analogous to Creatine Deficiency Syndrome (Yang et al., 2024). Our efforts are currently focused on delineating the molecular mechanism by which DcpS decapping contributes to creatine deficiency and neural function in human cognition.

          Nudt2 Decapping: We and others have reported mutations in the NUDT2 gene encoding the Nudix hydrolase 2 (Nudt2) have a causal link to neurodevelopmental disorders. We demonstrated that these mutations disrupt the mRNA decapping activity of Nudt2, resulting in the elevation of a subset of target mRNAs (Husain et al., 2024). Current efforts are focused on understanding the role of Nudt2 in neural differentiation and the molecular mechanism by which in impacts neurogenesis and cognition.

            RNA glycosylation targeting to extracellular exosomes: RNA modifications have long been known to influence the fate and function of coding and noncoding RNAs. We have identified a sugar modification of small noncoding RNAs (glycoRNA) that appears to target the RNA to extracellular vesicle (exosomes) (Sharma et al., 2024). These glycoRNAs can be transmitted intercellularly providing an avenue of RNA delivery through exosomes. We are in the process of determining how the glyco modification is added selectively to a subset of RNAs and how to leverage the process for therapeutic RNA delivery using these natural “lipid nanoparticle” exosomes.

            Non-canonical 5´-end caps; NAD caps. Another exciting finding from the lab is the demonstration that mammalian RNA can possess an alternative cap consisting of NAD instead of the m7G-cap at the 5´ end that can be added by a novel NAD cap addition (NADding) mechanism (Jiao et al. 2017). Furthermore, we have identified that remove the NAD cap (deNADding) to facilitate RNA degradation. Unlike the canonical cap, the NAD cap does not support mRNA translation and surprisingly, promotes rapid mRNA decay. Moreover, NAD cap levels are altered following cellular exposure to environmental stress indicating an important correlation between stress and NAD capping (Grudzien-Nogalsk et al. 2019). These findings present a transformative mode of 5´ end epitranscriptomic RNA modification and a new modulatory network potentially linking RNA metabolism to cellular energetics and stress (Kiledjian, 2018) that is being pursued.