Downregulation of multiple stress defense mechanisms during differentiation of human embryonic stem cells.
Evolutionary theory predicts that cellular maintenance, stress defense, and DNA repair mechanisms should be most active in germ line cells, including embryonic stem cells that can differentiate into germ line cells, whereas it would be energetically unfavorable to keep these up in mortal somatic cells. We tested this hypothesis by examining telomere maintenance, oxidative stress generation, and genes involved in antioxidant defense and DNA repair during spontaneous differentiation of two human embryonic stem cell lines. Telomerase activity was quickly downregulated during differentiation, probably due to deacetylation of histones H3 and H4 at the hTERT promoter and deacetylation of histone H3 at hTR promoter. Telomere length decreased accordingly. Mitochondrial superoxide production and cellular levels of reactive oxygen species increased as result of increased mitochondrial biogenesis. The expression of major antioxidant genes was downregulated despite this increased oxidative stress. DNA damage levels increased during differentiation, whereas expression of genes involved in different types of DNA repair decreased. These results confirm earlier data obtained during mouse embryonic stem cell differentiation and are in accordance with evolutionary predictions.
Crucible Lab, Institute of Human Genetics, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom. gabriele.saretzki@ncl.ac.uk
Gabriele
G
Saretzki
Theresia
T
Walter
Stuart
S
Atkinson
Jõao F
JF
Passos
Bettina
B
Bareth
W Nicol
WN
Keith
Rebecca
R
Stewart
Stacey
S
Hoare
Miodrag
M
Stojkovic
Lyle
L
Armstrong
Thomas
T
von Zglinicki
Majlinda
M
Lako
D000975:Antioxidants / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics* / Q000502:physiology*; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D015536:Down-Regulation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D016615:Telomere / Q000235:genetics / Q000378:metabolism
D000975:Antioxidants; D017382:Reactive Oxygen Species