Epitranscriptomics: new players in an old game.

Ageing is a conserved and unavoidable biological process characterized by progressive decline of physiological functions with time. Despite constituting the greatest risk factor for most human diseases, little is known about the molecular mechanisms driving the ageing process. More than 170 chemical RNA modifications, also known as the epitranscriptome, decorate eukaryotic coding and non-coding RNAs and have emerged as novel regulators of RNA metabolism, modulating RNA stability, translation, splicing or non-coding RNA processing. Studies on short-lived organisms such as yeast or worms connect mutations on RNA modifying enzymes with lifespan changes, and dysregulation of the epitranscriptome has been linked to age-related diseases and ageing hallmarks themselves in mammals. Moreover, transcriptome-wide analyses are starting to reveal changes in messenger RNA modifications in neurodegenerative diseases and in the expression of some RNA modifiers with age. These studies are starting to put the focus on the epitranscriptome as a potential novel regulator of ageing and lifespan, and open new avenues for the identification of targets to treat age-related diseases. In this review, we discuss the connection between RNA modifications and the enzymatic machinery regulating their deposition in coding and non-coding RNAs, and ageing and hypothesize about the potential role of RNA modifications in the regulation of other ncRNAs playing a key role in ageing, such as transposable elements and tRNA fragments. Finally, we reanalyze available datasets of mouse tissues during ageing and report a wide transcriptional dysregulation of proteins involved in the deposition, removal or decoding of several of the best-known RNA modifications.

BMAL1 coordinates energy metabolism and differentiation of pluripotent stem cells.

BMAL1 is essential for the regulation of circadian rhythms in differentiated cells and adult stem cells, but the molecular underpinnings of its function in pluripotent cells, which hold a great potential in regenerative medicine, remain to be addressed. Here, using transient and permanent loss-of-function approaches in mouse embryonic stem cells (ESCs), we reveal that although BMAL1 is dispensable for the maintenance of the pluripotent state, its depletion leads to deregulation of transcriptional programs linked to cell differentiation commitment. We further confirm that depletion of Bmal1 alters the differentiation potential of ESCs in vitro. Mechanistically, we demonstrate that BMAL1 participates in the regulation of energy metabolism maintaining a low mitochondrial function which is associated with pluripotency. Loss-of-function of Bmal1 leads to the deregulation of metabolic gene expression associated with a shift from glycolytic to oxidative metabolism. Our results highlight the important role that BMAL1 plays at the exit of pluripotency in vitro and provide evidence implicating a non-canonical circadian function of BMAL1 in the metabolic control for cell fate determination.