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From Exploring CGI Protection to Epigenomic Editing in Pluripotent Stem Cells

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Review of “Integration of CpG-free DNA induces de novo methylation of CpG islands in pluripotent stem cells” from Science by Stuart P. Atkinson

While the vast majority of the human genome lies in a highly methylated state, promoter-associated regions known as CpG islands (CGIs) tend to lack methylated cytosine residues [1-3]. Quite how these areas remain unmethylated in the surrounding “sea” of methylation remains an open question and one which the team of Juan Carlos Izpisua Belmonte (Salk Institute for Biological Studies, CA, USA) sought to answer in a new Science study. 

However, while exploring CGI protection, Takahashi et al. “drifted” towards a means to edit the epigenome of pluripotent stem cells (PSCs) in a targeted manner, and with it,  create cancer-related epimutation models and correct aberrant imprinting [4]!

Initial studies investigated the consequence of CpG-free DNA sequence integration into the unmethylated CGI of several active genes in human embryonic stem cells (hESCs). Interestingly, the introduction of a strictly CpG-free sequence and a state of transcriptional repression promoted the de novo methylation of the entire CGI, which remained stable after extensive passaging and differentiation. 

While these findings may help the authors to decipher the intricate mechanisms that control CGI protection, they also indicated that CpG-free DNA sequence integration might find use as a means to edit the epigenome!

To create a PSC epimutation model, the study targeted the CGI of the MLH1 DNA mismatch repair gene for DNA methylation. While the CGIs of both MLH1 alleles are normally unmethylated in a healthy individual, an epimutation event can lead to the methylation of one CGI and an increase in the risk of colorectal cancer [5]. Therefore, CpG-free DNA sequence integration in PSCs can allow us to model this cancer-related epimutation with relative ease.

The authors then generated induced pluripotent stem cells (iPSCs) from a patient with Angelman syndrome (AS), a complex genetic disorder in which a loss of DNA methylation (aberrant imprinting) eventually leads to the depletion of the ubiquitin-protein ligase E3A (UBE3A) in neural cells [6]. Exactingly, the integration of a CpG-free DNA sequence into the site of interest promoted de novo DNA methylation, the correction of aberrant imprinting status, and permitted the restoration of UBE3A expression in neurons differentiated from AS-iPSCs.

From basic research to a potentially exciting means to edit the epigenome! Keep tuned to the Stem Cells Portal to keep up to date with all the news studies related to this exciting new study!

References

  1. Gifford CA, Ziller MJ, Gu H, et al. Transcriptional and epigenetic dynamics during specification of human embryonic stem cells. Cell 2013;153:1149-1163.
  2. Guo H, Zhu P, Yan L, et al. The DNA methylation landscape of human early embryos. Nature 2014;511:606-610.
  3. Xie W, Schultz MD, Lister R, et al. Epigenomic analysis of multilineage differentiation of human embryonic stem cells. Cell 2013;153:1134-1148.
  4. Takahashi Y, Wu J, Suzuki K, et al. Integration of CpG-free DNA induces de novo methylation of CpG islands in pluripotent stem cells. Science 2017;356:503-508.
  5. Hitchins M, Williams R, Cheong K, et al. MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer. Gastroenterology 2005;129:1392-1399.
  6. Kishino T, Lalande M, and Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet 1997;15:70-73.