LSD1/KDM1A Maintains Genome-wide Homeostasis of Transcriptional Enhancers

Transcriptional enhancers enable exquisite spatiotemporal control of gene expression in metazoans. Enrichment of mono-methylation of histone H3 lysine 4 (H3K4me1) is a major chromatin signature that distinguishes enhancers from gene promoters. Lysine Specific Demethylase 1 (LSD1, aka KDM1A), an enzyme specific for demethylating H3K4me2/me1, has been shown to \"decommission\" stem cell enhancers during the differentiation of mouse embryonic stem cells (mESC). However, the roles of LSD1 in undifferentiated mESC remain obscure. Here, we show that LSD1 occupies a large fraction of enhancers (63%) that are primed with binding of transcription factors (TFs) and H3K4me1 in mESC. In contrast, LSD1 is largely absent at latent enhancers, which are not yet primed by TF binding. Unexpectedly, LSD1 levels at enhancers exhibited a clear positive correlation with its substrate, H3K4me2 and enhancer activity. These enhancers gain additional H3K4 methylation upon the loss of LSD1 in mESC. The aberrant increase in H3K4me at enhancers was accompanied with increases in enhancer H3K27 acetylation and expression of enhancer RNAs (eRNAs) and their target genes. In post-mitotic neurons, loss of LSD1 resulted in premature activation of enhancers and genes that are normally induced after neuronal activation. These results demonstrate that LSD1 is a versatile suppressor of primed enhancers, and is involved in homeostasis of enhancer activity.