LSD1/KDM1 regulates the balance between self-renewal and differentiation in human embryonic stem cells.

Embryonic stem (ES) cells have the ability to differentiate into all the cell types of the adult organism. This unusual property has been proposed to emanate from a particular chromatin environment that simultaneously contains both H3K4 and H3K27 trimethylation marks at the regulatory regions of the developmental genes, which are thus poised for activation during differentiation following resolution of these “bivalent domains.” Our work identifies Lysine Specific Demethylase 1 (LSD1/AOF2/KDM1A) as a key histone modifier in the maintenance of pluripotency. We show that the knock-down of LSD1 causes the differentiation of human ES cells and the induction of key endo- and mesodermal genes marked with bivalent domains. This induction correlates with an increase in the levels of H3K4 methylation at the regulatory regions of these genes. ChIP on chip analysis reveals that in human ES cells LSD1 preferentially occupies the promoters of a subset of developmental genes that contain bivalent domains that are also occupied by OCT4 and NANOG. We conclude that LSD1 contributes to maintain a subset of developmental genes in human ES in a silenced state by maintaining the critical balance between H3K4 and H3K27 methylation at the regulatory regions of these genes. Lsd1 binding sites in human embryonic stem cells have been determined by ChIP on chip, and gene expression changes upon Lsd1 knock down have been tracked by microarray profiling.