CONICET | Buscador de Institutos y Recursos Humanos

TERRAs (telomeric repeat containing RNAs), are long non-coding RNAs associated with telomere and genome stability. Telomeres are particularly prone to be damaged by oxidative stress and, thus their protection is relevant to avoid their dysfunction. We showed that the level of TERRAs are increased in response to oxidative stress as a mechanism of telomere protection. However, ROS have proven to be signaling molecules, and we found that physiologic increase of ROS in brown adipose tissue of mice exposed to cold triggered the induction of TERRAs. It is also well known that ROS increase during adipocyte differentiation. We found that TERRAs increased their level of expression during the differentiation of 3T3-L1 preadipocytes. Their increase was prevented in the presence of the antioxidant N-acetyl-L-cysteine. Next, we tested which component of the adipogenic cocktail (MDI: IBMX, DEXA, Insulin, Rosiglitazone) was responsible for TERRAs induction, and TERRAs increased upon IBMX or rosiglitazone treatment of 3T3-L1 preadipocytes. Further, PKA inhibitors H89 and PKI blocked the increase of TERRA induced by MDI as well as the increased mediated by IBMX or rosiglitazone treatments, suggesting that TERRA induction is under PKA control. We analyzed the formation of telomere-associated DNA damage foci (TAFs) in 3T3-L1 preadipocytes induced to differentiate by IIF labelling TRF1, a component of the sheltering complex in telomeres and gH2AX, the phosphorylated histone variant found at sites of DNA damage. No colocalization was observed between TRF1 and gH2AX in images obtained by confocal microscopy indicating no TAF formation, thus the telome integrity was preserved during adipogenesis. In summary, we showed for the first time that TERRAs are induced during the process of adipocyte differentiation dependent on ROS and PKA signaling in order to protect telomers and possibly having other potential functions that need to be unveiled