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While the transcriptional network of human embryonic stem cells (hESCs) has been extensively studied, relatively little is known about how post-transcriptional modulations determine hESC function. RNA-binding proteins play central roles in RNA regulation, including translation and turnover. Here we show that the RNA-binding protein CSDE1 (cold shock domain containing E1) is highly expressed in hESCs to maintain their undifferentiated state and prevent default neural fate. Notably, loss of CSDE1 accelerates neural differentiation and potentiates neurogenesis. Conversely, ectopic expression of CSDE1 impairs neural differentiation. We find that CSDE1 post-transcriptionally modulates core components of multiple regulatory nodes of hESC identity, neuroectoderm commitment and neurogenesis. Among these key pro-neural/neuronal factors, CSDE1 binds fatty acid binding protein 7 (FABP7) and vimentin (VIM) mRNAs, as well as transcripts involved in neuron projection development regulating their stability and translation. Thus, our results uncover CSDE1 as a central post-transcriptional regulator of hESC identity and neurogenesis. [ABSTRACT FROM AUTHOR]

Cardiac dysfunctions dramatically increase with age. Revealing a currently unknown contributor to cardiac ageing, we report the age‐dependent, cardiac‐specific accumulation of the lysosphingolipid sphinganine (dihydrosphingosine, DHS) as an evolutionarily conserved hallmark of the aged vertebrate heart. Mechanistically, the DHS‐derivative sphinganine‐1‐phosphate (DHS1P) directly inhibits HDAC1, causing an aberrant elevation in histone acetylation and transcription levels, leading to DNA damage. Accordingly, the pharmacological interventions, preventing (i) the accumulation of DHS1P using SPHK2 inhibitors, (ii) the aberrant increase in histone acetylation using histone acetyltransferase (HAT) inhibitors, (iii) the DHS1P‐dependent increase in transcription using an RNA polymerase II inhibitor, block DHS‐induced DNA damage in human cardiomyocytes. Importantly, an increase in DHS levels in the hearts of healthy young adult mice leads to an impairment in cardiac functionality indicated by a significant reduction in left ventricular fractional shortening and ejection fraction, mimicking the functional deterioration of aged hearts. These molecular and functional defects can be partially prevented in vivo using HAT inhibitors. Together, we report an evolutionarily conserved mechanism by which increased DHS levels drive the decline in cardiac health. Synopsis: The metabolite dihydrosphingosine (DHS), a potent HDAC inhibitor, accumulates in the heart in an age‐dependent manner. Elevated DHS levels result in cellular transcription‐dependent DNA damage, which ultimately causes ageing‐associated cardiac insufficiencies. Elevated sphinganine (DHS) levels is an evolutionarily conserved hallmark of cardiac ageing, including humans.Elevated DHS levels cause DNA damage in cardiomyocytes in vitro and in vivo.DHS derivative DHS1P is a potent HDAC inhibitor causing histone hyperacetylation and increased transcription, leading to DNA damage.Exogenous increase of DHS levels in young adult mice causes ageing‐associated functional impairment of the heart.Restoring histone acetylation levels by HAT inhibition prevents DHS‐induced cardiac DNA damage and functional impairment in vivo. The metabolite dihydrosphingosine (DHS), a potent HDAC inhibitor, accumulates in the heart in an age‐dependent manner. Elevated DHS levels result in cellular transcription‐dependent DNA damage, which ultimately causes ageing‐associated cardiac insufficiencies. [ABSTRACT FROM AUTHOR]