Table 1.
Function of selected epigenetic regulators in mouse pluripotent ES cells
| Gene | Gene product | Mouse mutant | Function in ES cells | Phenotype of mouse germline mutation | Reference (s) |
|---|---|---|---|---|---|
| Brg1 | SWI/SNF subunit, ATPase | null and KD | Required for ES cell SR and pluripotency. Required for survival of the ICM and trophectoderm. KO ES cells cannot be derived from blastocysts* | KO embryos die during the pre-implantation stage | Bultman et al. (2000, 2006), Ho et al. (2009a,b), Kidder et al. (2009) |
| BAF250a/Arid1a | SWI/SNF subunit | null | Required for ES cell pluripotency, SR and differentiation. KO ES cells are impaired in their ability to differentiate into functional mesoderm-derived cardiomyocytes and adipocytes but are capable of differentiating into ectoderm-derived neurons. KO ES cells are prone to differentiate into primitive endoderm-like cells under normal feeder-free culture conditions | KO embryos arrest development at E6.5; they form the ICM but do not gastrulate or form mesoderm | Gao et al. (2008) |
| BAF250b/Arid1b | SWI/SNF subunit | null | Required for ES cell SR and proliferation. KO ES cells show a mild reduction in proliferation and more rapid differentiation | N/A; biallelic inactivation in ES cells | Yan et al. (2008) |
| BAF155/Srg3 | SWI/SNF subunit | null | Required for ICM outgrowth. KO ES cells cannot be derived from blastocysts* | KO embryos develop in the early implantation stage but undergo rapid degeneration thereafter | Kim et al. (2001) |
| BAF47/Snf5/ini1 | SWI/SNF subunit | null | Required for ICM outgrowth and formation of trophectoderm. KO ES cells cannot be derived from blastocysts* | KO embryos die between E3.5 and E5.5 at the periimplantation stage | Klochendler-Yeivin et al. (2000), Guidi et al. (2001) |
| Snf2h | ISWI subunit, ATPase | null | Required for survival and growth of trophectoderm and ICM | KO embryos die during the periimplantation stage | Stopka & Skoultchi (2003) |
| Bptf | ISWI subunit | null | Required for ES cell differentiation. KO ES cells are deficient in their ability to form the mesodermal, endodermal, and ectodermal lineages | KO embryos manifest growth defects at the postimplantation stage and are reabsorbed by E8.5 | Landry et al. (2008) |
| Mbd3 | NuRD subunit | null | Required for ES cell pluripotency. KO ES cells can be maintained in the absence of leukemia inhibitory factor (LIF) and initiate differentiation in embryoid bodies or chimeric embryos, but fail to commit to specific lineages. ICM of KO blastocysts fails to develop into mature epiblast after implantation | KO embryos die at around the time of implantation | Kaji et al. (2006, 2007) |
| Ring1b/Rnf2 | Polycomb group, PRC1, H2A E3 monoubiquitin ligase | null | Required to stably maintain undifferentiated state of mouse ES cells | KO embryos show gastrulation arrest | Voncken et al. (2003), van der Stoop et al. (2008), Roman-Trufero et al. (2009) |
| Ezh2/Enx1 | Polycomb group, PRC2, H3K27 HMTase | null | KO ES cells can be derived from blastocysts as well as self-renew | KO embryos stop developing after implantation or fail to complete gastrulation and die at around E8.5 | Shen et al. (2008) |
| Eed | Polycomb group, PRC2 | null | Eed null ES cells are pluripotent, even though they have a tendency to differentiate spontaneously in culture and display midly defective differentiation. Eed null chimeras have a paucity of mesoderm | KO embryos die at around E8.5 with all germ layers formed but defects in mesoderm formation | Faust et al. (1995), Montgomery et al. (2005) |
| Suz12 | Polycomb group, PRC2 | null | Required for ES cell differentiation in culture. KO ES cells cannot form neurons after in vitro differentiation and KO EBs fail to form a proper endodermal layer | KO embryos die during early postimplantation stages | Pasini et al. (2004, 2007) |
| Yy1 | PRC2/3 interaction | null | KO ES cells cannot be derived from blastocysts* | KO embryos die at around the time of implantation | Donohoe et al. (1999) |
| Jarid2/jumonji | Histone demethylase of jumonji family, PRC2 subunit | null | Required for ES cell differentiation. Modulates the balance between SR and differentiation. Lineage commitments are delayed in KO ES cells | KO embryos die before E15.5, required for neural tube formation | Takeuchi et al. (1995, 1999), Shen et al. (2009), Pasini et al. (2010) |
| Mll2/Wbp7 | H3K4 HMTase | null | Required for ES cell proliferation, proper differentiation and survival but dispensable for SR and pluripotency | KO embryos fail to develop beyond around E9.5 | Glaser et al. (2006), Lubitz et al. (2007) |
| G9a/Ehmt2 | H3K9 HMTase | null | KO ES cells exhibit growth defects upon induction of differentiation with all-trans retinoic acid (RA) | KO embryos die at around E8.5–E9.5 | Tachibana et al. (2002, 2005) |
| Glp/Ehmt1 | H3K9 HMTase | null | N/A | KO embryos die at around E9.5 | Tachibana et al. (2005) |
| Eset/Setdb1 | H3K9 HMTase | null | Required for ICM outgrowth. KO ES cells cannot be derived from blastocysts* | KO embryos die at around E3.5–E5.5 | Dodge et al. (2004), Bilodeau et al. (2009) |
| Dnmt1 | Dnmt (maintenance) | null | Required for ES cell differentiation. KO ES cells proliferate normally but die upon induction of differentiation and cannot form teratomas | Development of KO embryos is arrested prior to the eight-somite stage | Lei et al. (1996), Tucker et al. (1996), Gaudet et al. (1998) |
| Dnmt3a/3b | Dnmt (de novo) | null | Required for ES cell differentiation. Late-passage KO ES cells cannot form teratomas | Dnmt3a KO mice become runted and die at around 4 weeks of age; Dnmt3b KO mice die after E9.5; dKO mice die before E11.5 | Okano et al. (1999), Chen et al. (2003) |
| Dnmt1/3a/3b | Dnmt | null | Modest effect on ES cell proliferation. Triple KO ES cells grow robustly (although slightly slower than WT) and maintain their undifferentiated characteristics | N/A; triple-KO ES cells were studied | Tsumura et al. (2006) |
| p300 | HAT and coactivator | null | Required for ES cell differentiation but dispensable for SR | KO embryos die at or before E11.5 | Yao et al. (1998), Zhong & Jin (2009) |
| Thap11/Ronin | Thap and ZF-domain epigenetic regulator | null and OE | Promotes ES cell SR/proliferation, essential for pluripotency. Required for ICM outgrowth. KO ES cells cannot be derived from blastocysts.* OE inhibits ES cell differentiation | KO embryos die at periimplantation | Dejosez et al. (2008) |
Abbreviations: dKO, double knockout; Dnmt, DNA methyltransferase; EB, embryoid body; ES, embryonic stem; HAT, histone acetyltransferase; ICM, inner cell mass; KD, knockdown; KO, knockout; N/A, not available; OE, overexpression; SR, self-renewal; WT, wild type; ZF, zinc finger.
*
Deletion of these genes causes a failure of the ICM to give rise to ES cells in vitro, suggesting a direct role in the establishment or maintenance of pluripotency.