snoRNAs and metabolic stress

Excess lipid accumulation in non-adipose tissues is associated with cellular dysfunction and cell death that is linked to the pathogenesis of complications of diabetes and obesity. Through a genetic screen in mammalian cells, we discovered that small nucleolar RNAs (snoRNAs) embedded within introns of host genes can serve as critical mediators in the propagation of oxidative stress and cell death in the response to lipotoxicity. The canonical function of these short non-coding RNAs is to direct 2'-O-methylation (box C/D snoRNAs) or pseudouridylation (box H/ACA snoRNAs) modifications of newly synthesized ribosomal RNAs in the nucleus. Our screen identified a family of box C/D snoRNAs in the Rpl13a locus (U32a, U33, U34, and U35a), as well as two box H/ACA snoRNAs in the Snhg3 locus (U17a and U17b) that have addition roles in metabolic regulation.

Through what mechanisms do these snoRNAs act in metabolic stress? We are using cell biological and biochemical approaches and high throughput RNA-sequencing to reveal the targets of these snoRNAs, and the consequences of target engagement for cellular metabolism and survival.

We are also investigating the metabolic roles of these and other snoRNAs. Our studies in cultured cells and in mice indicate that these snoRNAs have important roles in regulation of mitochondrial function and oxidative metabolism.

Do these snoRNAs contribute to disease progression? We have generated mouse models to test the contributions of these snoRNAs to the pathogenesis of diabetes complications.