The ATP dependent nucleosome remodeler Mi

The ATP-dependent nucleosome remodeler Mi2 is the core component of the nucleosome remodeling and deacetylase complex (NuRD), a multisubunit transcriptional repressor complex known to play a major role in mammalian cell fate determination and capable of different scopes of activities depending on its subunit content (reviewed in Bowen et al., 2004). Embryonic stem read review (ESCs) deficient for the NuRD subunit MBD3 are unable to undertake lineage commitment (Kaji et al., 2006). Conditional knockout mice models showed that Mi2/NuRD was essential in terminal differentiation programs, including T cell maturation (Williams et al., 2004) and Schwann cell-directed peripheral nerve myelination (Hung et al., 2012). In addition, recent findings propose that the NuRD repressive activity is required to limit pluripotency gene expression, thereby permitting ESC differentiation (Reynolds et al., 2012a). Recently, histone H3 lysine 4 (H3K4) demethylase LSD1/KMD1A was identified as a de novo member of the NuRD complex in HeLa cell extracts (Wang et al., 2009) and in ESCs (Whyte et al., 2012), independently of the chromatin repressor complex CoREST, of which it is the core component (Lee et al., 2005). LSD1 carries differentiation-licensing functions in common with the NuRD complex. lsd1−/− ESCs fail to fully deactivate pluripotency gene enhancers to complete differentiation programs (Whyte et al., 2012). LSD1 silences the bivalent promoter of developmental genes, which combine activating H3K4me2/3 and repressing H3K27me3 histone marks, to maintain ESC pluripotency (Adamo et al., 2011). LSD1 is also involved in multiple developmental programs, including myoblast differentiation (Choi et al., 2010) and neuronal development (Ceballos-Chávez et al., 2012; Fuentes et al., 2012), and is a putative metastatic breast cancer suppressor (Wang et al., 2009). In Drosophila, loss of LSD1 leads to ovarian germline tumorigenesis, because somatic gonadal cells become unable to produce the lineage specification signals required for germline stem cell differentiation (Eliazer et al., 2011). In C. elegans, homologs for both the NuRD complex and LSD1 were identified. C. elegans LET-418/Mi2 is a subunit of a NuRD-like complex, together with Rb-binding protein LIN-53/RbAp48, histone deacetylase HDA-1/HDAC1, metastasis-associated protein homolog LIN-40/MTA1, and DCP-66/p66(α/β) (Passannante et al., 2010; Unhavaithaya et al., 2002; our unpublished data). The C. elegans NuRD-like complex was previously involved in controlling the vulval cell fate (von Zelewsky et al., 2000). In addition, similar to its Drosophila dMi2 homolog (Kunert et al., 2009), LET-418 interacts tightly with the zinc finger protein MEP-1 and HDA-1/HDAC1 in a distinct MEP-1-interacting complex (MEC) involved in repressing germline gene expression in somatic cells (Passannante et al., 2010; Unhavaithaya et al., 2002). Three C. elegans genes encode putative LSD1 homologs: Suppressor of Presenilin 5 (spr-5), T08D10.2/lsd-1 and R13G10.2/amx-1. The SPR-5 protein displays a demonstrated biochemical H3K4 demethylase activity and functions in promoting fertility (Katz et al., 2009). SPR-5 is partially responsible for the specific erasure of H3K4me2 marks in the PGCs at their birth. spr-5 mutants progressively accumulate H3K4me2 in PGCs throughout generations, correlating with the progressive “mortal germline” sterile phenotype peaking at 28–30 generations (Katz et al., 2009). All these observations suggest that the functions of LSD1 and Mi2/NuRD in controlling cell lineage specification are ancient and well conserved across species. In order to decipher the molecular mechanisms by which LSD1 and NuRD determine cell fate in vivo, we set up to analyze their common functions in the developmental model organism C. elegans. Here, we describe an interaction between the C. elegans LET-418/Mi2-containing complexes and SPR-5/LSD1. In addition to the physical interaction between SPR-5, LET-418, and associated complexes, spr-5 and let-418 interact genetically to promote the normal development of germline stem cells. Concomitant loss of SPR-5 and LET-418 leads to immediate sterility, aberrant gonad development, and germline teratoma incidence. SPR-5 and LET-418 together maintain the germline stem cell status and form an epigenetic barrier to reprogramming. This infers the existence of a conserved link between LSD1 and Mi2-related complexes and shows that specific epigenetic regulators collaborate intricately to control cell fate during germ cell development.