Editing Embryonic stem cell (section)

=== Growth ===

ESCs divide very frequently due to a shortened [[G1 phase]] in their [[cell cycle]]. Rapid [[cell division]] allows the cells to quickly grow in number, but not size, which is important for early embryo development. In ESCs, [[cyclin A]] and [[cyclin E]] proteins involved in the [[G1/S transition]] are always expressed at high levels.<ref name="Boward">{{cite journal|pmid=26889666|pmc=5201256|year=2016|last1=Boward|first1=B.|title=Concise Review: Control of Cell Fate Through Cell Cycle and Pluripotency Networks|journal=Stem Cells|volume=34|issue=6|pages=1427–36|last2=Wu|first2=T.|last3=Dalton|first3=S.|doi=10.1002/stem.2345}}</ref> [[Cyclin-dependent kinase]]s such as [[CDK2]] that promote cell cycle progression are overactive, in part due to downregulation of their inhibitors.<ref>{{cite journal|pmid=15703208|pmc=1073679|year=2005|last1=White|first1=J.|title=Developmental activation of the Rb-E2F pathway and establishment of cell cycle-regulated cyclin-dependent kinase activity during embryonic stem cell differentiation|journal=Molecular Biology of the Cell|volume=16|issue=4|pages=2018–27|last2=Stead|first2=E.|last3=Faast|first3=R.|last4=Conn|first4=S.|last5=Cartwright|first5=P.|last6=Dalton|first6=S.|doi=10.1091/mbc.e04-12-1056}}</ref> [[Retinoblastoma protein]]s that inhibit the [[transcription factor]] [[E2F]] until the cell is ready to enter [[S phase]] are hyperphosphorylated and inactivated in ESCs, leading to continual expression of proliferation genes.<ref name="Boward" /> These changes result in accelerated cycles of cell division. Although high expression levels of pro-proliferative proteins and a shortened G1 phase have been linked to maintenance of pluripotency,<ref>{{Cite journal|last1=Ter Huurne|first1=Menno|last2=Stunnenberg|first2=Hendrik G.|date=21 April 2021|title=G1-phase progression in pluripotent stem cells|journal=Cellular and Molecular Life Sciences|volume=21|issue=10|pages=4507–4519|doi=10.1007/s00018-021-03797-8|issn=1875-9777|pmid=33884444|pmc=8195903|doi-access=free}}</ref><ref>{{Cite journal|last1=Singh|first1=Amar M.|last2=Dalton|first2=Stephen|date=2009-08-07|title=The cell cycle and Myc intersect with mechanisms that regulate pluripotency and reprogramming|journal=Cell Stem Cell|volume=5|issue=2|pages=141–149|doi=10.1016/j.stem.2009.07.003|issn=1875-9777|pmc=2909475|pmid=19664987}}</ref> ESCs grown in serum-free 2i conditions do express hypo-phosphorylated active Retinoblastoma proteins and have an elongated G1 phase.<ref>{{Cite journal|last1=Ter Huurne|first1=Menno|last2=Chappell|first2=James|last3=Dalton|first3=Stephen|last4=Stunnenberg|first4=Hendrik G.|date=5 October 2017|title=Distinct Cell-Cycle Control in Two Different States of Mouse Pluripotency|journal=Cell Stem Cell|volume=21|issue=4|pages=449–455.e4|doi=10.1016/j.stem.2017.09.004|issn=1875-9777|pmc=5658514|pmid=28985526}}</ref> Despite this difference in the cell cycle when compared to ESCs grown in media containing serum these cells have similar pluripotent characteristics.<ref>{{Cite journal|last1=Ying|first1=Qi-Long|last2=Wray|first2=Jason|last3=Nichols|first3=Jennifer|last4=Batlle-Morera|first4=Laura|last5=Doble|first5=Bradley|last6=Woodgett|first6=James|last7=Cohen|first7=Philip|last8=Smith|first8=Austin|date=2008-05-22|title=The ground state of embryonic stem cell self-renewal|journal=Nature|volume=453|issue=7194|pages=519–523|doi=10.1038/nature06968|issn=1476-4687|pmc=5328678|pmid=18497825|bibcode=2008Natur.453..519Y}}</ref> Pluripotency factors [[Oct4]] and [[Homeobox protein NANOG|Nanog]] play a role in transcriptionally regulating the embryonic stem cell cycle.<ref>{{cite journal|pmid=19968627|pmc=2825734|year=2010|last1=Lee|first1=J.|title=Oct-4 controls cell-cycle progression of embryonic stem cells|journal=The Biochemical Journal|volume=426|issue=2|pages=171–81|last2=Go|first2=Y.|last3=Kang|first3=I.|last4=Han|first4=Y. M.|last5=Kim|first5=J.|doi=10.1042/BJ20091439}}</ref><ref>{{cite journal|pmid=19139263|pmc=2615089|year=2009|last1=Zhang|first1=X.|title=A role for NANOG in G1 to S transition in human embryonic stem cells through direct binding of CDK6 and CDC25A|journal=The Journal of Cell Biology|volume=184|issue=1|pages=67–82|last2=Neganova|first2=I.|last3=Przyborski|first3=S.|last4=Yang|first4=C.|last5=Cooke|first5=M.|last6=Atkinson|first6=S. P.|last7=Anyfantis|first7=G.|last8=Fenyk|first8=S.|last9=Keith|first9=W. N.|last10=Hoare|first10=S. F.|last11=Hughes|first11=O.|last12=Strachan|first12=T.|last13=Stojkovic|first13=M.|last14=Hinds|first14=P. W.|last15=Armstrong|first15=L.|last16=Lako|first16=M.|doi=10.1083/jcb.200801009}}</ref>