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  • The EMBO Journal (2006) 25, 5329 - 5338
  • doi:10.1038/sj.emboj.7601399

Published online: 2 November 2006

Correction of aberrant imprinting of IGF2 in human tumors by nuclear transfer-induced epigenetic reprogramming

Hui Ling Chen1,2,5, Tao Li1,3,5, Xin Wen Qiu1,3, Jie Wu4, Jian Qun Ling1,3, Zhi Hong Sun4, Weibo Wang2, Wei Chen1, Aiju Hou3, Thanh H Vu1,3, Andrew R Hoffman1,3,6 and Ji-Fan Hu1,4,6

  1. Medical Service, VA Palo Alto Health Care System, Palo Alto, CA, USA
  2. Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, Hunan Province, PR China
  3. Department of Medicine, Stanford University Medical School, Palo Alto, CA, USA
  4. GMR Epigenetics Corporation, Palo Alto, CA, USA
  5. These authors contributed equally to this work
  6. These authors are senior authors of this report

Correspondence to:

Andrew R Hoffman, Department of Medicine, Stanford University Medical School, Palo Alto, CA 94304, USA. Tel.: +1 650 858 3930; Fax: +1 650 856 8024; E-mail: arhoffman@stanford.edu

Ji-Fan Hu, Department of Medicine, PAIRE, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA. Tel.: +1 650 493 5000 x 63175; Fax: +1 650 856 8024; E-mail: jifan@stanford.edu

Received 1 June 2006; Accepted 27 September 2006

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.

  • Keywords:

    • CTCF,
    • DNA methylation,
    • IGF2,
    • imprinting,
    • nuclear transfer