Lysine-Specific Demethylase 1 Regulates the Embryonic Transcriptome and CoREST Stability

Abstract

Lysine-specific demethylase 1 (LSD1), which demethylates mono-and dimethylated histone H3-Lys4 as part of a complex including CoREST and histone deacetylases (HDACs), is essential for embryonic development in the mouse beyond embryonic day 6.5 (e6.5). To determine the role of LSD1 during this early period of embryogenesis, we have generated loss-of-function gene trap mice and conditional knockout embryonic stem ( The methylation of lysine residues within histones H3 and H4 helps to regulate the higher-order structure of chromatin in eukaryotic genomes. The consequences of lysine methylation on gene expression (unlike acetylation) can be either positive or negative, depending on the context of a particular lysine residue and the number of methyl moieties added (24, 27). Trimethylation of K9 on histone H3 (H3K9me3), for example, is generally associated with silenced genes and constitutive heterochromatin. In contrast, trimethylation of K4 on the same histone, H3 (H3K4me3), is associated with transcriptionally active regions. These methylated lysine residues provide the docking sites for the subsequent binding of chromatin-associated proteins with a cognate chromodomain, plant homeo domain (PHD) finger, or Tudor domain (42). Thus, the four methylated states of each specific lysine (unmodified or mono-, di-, or trimethylated) are interpreted by the association of other factors, such as the binding of HP1␣ to trimethyl H3 Lys9 (3, 29), which modify chromatin directly or indirectly. Lysine methylation in vivo is controlled by the opposing activities of lysine methyltransferases (KMTs) and lysine demethylases (KDMs). KDMs appear in two varieties: the amine oxidases, of which there are two (lysine-specific demethylase 1

Lysine-specific demethylase 1 regulates differentiation onset and migration of trophoblast stem cells

“…1b for schematic of the different embryonic cell types). Consistent with previous reports [19][20][21][22] , we find that Lsd1 À / À embryos are significantly reduced in size but possess cells of the three early embryonic lineages, namely epiblast, extraembryonic ectoderm and primitive endoderm/visceral endoderm as shown by haematoxylin and eosin (HE) staining (Fig. 1b).…”

“…To specifically dissect Lsd1 functions in the different cell lineages of the pregastrula stage mouse embryo, we engineered a novel conditional Lsd1 allele by flanking exon 1 with loxP sites. In agreement with earlier reports [19][20][21][22] , ubiquitous deletion of the conditional Lsd1 allele (Lsd1 À / À ) leads to early embryonic lethality, and only resorbed embryos are detected by E7.5 (Fig. 1a).…”

“…Several studies have reported functions of Lsd1 in ESCs and in the early epiblast [19][20][21][22][23][24] . Whether or not absence of Lsd1 in the epiblast indeed accounts for the early embryonic lethality of Lsd1-deficient embryos preceding E7.5 has not been conclusively addressed.…”

“…5 (refs 19-22) proposing predominant functions in pluripotent cells of the epiblast. Analysis of Lsd1-deficient mouse embryonic stem cells in culture suggested a progressive loss of DNA methylation 19 , altered expression of genes crucial for ES cell differentiation 21 or a bias towards extraembryonic lineage differentiation 20 . Furthermore, Adamo et al 23 reported that LSD1 regulates the balance between self-renewal and differentiation of human ESCs (hESCs).…”

Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs

“…Epigenetic intervention and/or HDAC inhibition have been recently identified as the critical determinant for cell programming in in vitro studies (16, 42, 44). Although we have (9,11,24,32). In this study, using the established siRNA approach, which is widely performed to knockdown specific genes in progenitor cells (17), we demonstrated that the treatment of HDAC4 siRNA significantly induced the knockdown of HDAC4 in c-kit ϩ CSCs, which is also accompanied by the reduction of HDAC activity.…”