Correction of aberrant imprinting of IGF2 in human tumors by nuclear transfer-induced epigenetic reprogramming.
Loss of genomic imprinting of insulin-like growth factor II (IGF2) is a hallmark of many human neoplasms. We attempted to correct this aberrant epigenotype by transferring nuclei from human tumor cells that showed loss of IGF2 imprinting into enucleated mouse and human fibroblasts that had maintained normal IGF2 imprinting. After nuclear transfer, the abnormal biallelic expression of IGF2 in tumor nuclei transiently converted to normal monoallelic imprinted expression in the reconstructed diploid cells. In tetraploid hybrid cells, however, normal IGF2 imprinting was permanently restored in the tumor genome. Inhibition of the synthesis of putative trans imprinting factors with cycloheximide led to loss of IGF2 imprinting in normal cultured fibroblasts, suggesting that normal cells produce proteins that act in trans to induce or maintain genomic imprinting. These data demonstrate that an abnormal tumor epigenotype can be corrected by in vitro reprogramming, and suggest that loss of imprinting is associated with the loss of activity of non-CTCF trans imprinting factor(s) that are either inactivated or mutated in tumors.
Chen
Hui Ling
HL
Medical Service, VA Palo Alto Health Care System, Palo Alto, CA, USA.
Li
Tao
T
Qiu
Xin Wen
XW
Wu
Jie
J
Ling
Jian Qun
JQ
Sun
Zhi Hong
ZH
Wang
Weibo
W
Chen
Wei
W
Hou
Aiju
A
Vu
Thanh H
TH
Hoffman
Andrew R
AR
Hu
Ji-Fan
JF
D000818:Animals; D000076246:CCCTC-Binding Factor; D002460:Cell Line; D045744:Cell Line, Tumor; D003513:Cycloheximide / Q000494:pharmacology; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D052138:Genes, Neoplasm; D018392:Genomic Imprinting; D006801:Humans; D006822:Hybrid Cells; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D053652:Nuclear Transfer Techniques; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; C000619698:Ctcf protein, mouse; D004268:DNA-Binding Proteins; D011500:Protein Synthesis Inhibitors; D012097:Repressor Proteins; D007335:Insulin-Like Growth Factor II; D003513:Cycloheximide