A crucial feature of differentiated cells is the rapid activation of enhancer-driven transcriptional programs in response to signals. The potential contributions of physicochemical properties of

We report that a neuron-specific isoform of LSD1, LSD1n, resulting from an alternative splicing event, acquires a novel substrate specificity targeting histone H4 K20 methylation, both in vitro and in vivo. Selective genetic ablation of LSD1n leads to deficits in spatial learning and memory, revealing the functional importance of LSD1n in the regulation of neuronal activity-regulated transcription in a fashion indispensable for long-term memory formation. LSD1n occupies neuronal gene enhancers, promoters and transcribed coding regions, and is required for transcription initiation and elongation steps in response to neuronal activity, indicating the crucial role of H4K20 methylation in coordinating gene transcription with neuronal function. This study reveals that the alternative splicing of LSD1 in neurons, associated with altered substrate specificity, serves as an underlying mechanism acquired by neurons to achieve more precise control of gene expression in the complex processes underlying learning and memory.

SUMMARY Pancreatic beta-cell mass for appropriate blood glucose control is established during early postnatal life. Beta-cell proliferative capacity declines postnatally but the extrinsic cues and intracellular signals that cause this decline remain unknown. To obtain a high-resolution map of beta-cell transcriptome dynamics after birth, we generated single-cell RNA-seq data of beta-cells from multiple postnatal time points and ordered cells based on transcriptional similarity using a new analytical tool. This analysis captured signatures of immature, proliferative beta-cells and established high expression of amino acid metabolic, mitochondrial, and Srf/Jun/Fos transcription factor genes as their hallmark feature. Experimental validation revealed high metabolic activity in immature beta-cells and a role for reactive oxygen species and Srf/Jun/Fos transcription factors in driving postnatal beta-cell proliferation and mass expansion. Our work provides the first high-resolution molecular characterization of state changes in postnatal beta-cells and paves the way for the identification of novel therapeutic targets to stimulate beta-cell regeneration.