BioTech IP Review

CRISPR/dCas9 DNA methylation editing is heritable during human hematopoiesis and shapes immune progeny

  • Journal: Proceedings of the National Academy of Sciences (PNAS)
  • Publication Date: August 14, 2023
  • DOI: 10.1073/pnas.2300224120
  • Authors: Emily A. Saunderson, Hector Huerga Encabo, Julie Devis, Kevin Rouault‑Pierre, Marion Piganeau, Christopher G. Bell, John G. Gribben, Dominique Bonnet & Gabriella Ficz (et al.) 

What This Study Covers

This study demonstrates that targeted DNA methylation editing using a “dead” CRISPR‑Cas9 (dCas9) fused to DNA methyltransferase enzymes can create stable, heritable changes in epigenetic state in human hematopoietic stem and progenitor cells (HSPCs). Specifically:

  • The researchers directed DNA methylation to promoters of tumor suppressor genes (e.g., p15, p14) in human HSPCs using CRISPR/dCas9 fused to DNA methyltransferase domains.
  • They showed that the introduced DNA methylation was maintained during differentiation into mature blood cell lineages both in vitro and in vivo after engraftment into mouse bone marrow.
  • These engineered epigenetic changes altered the abundance and activation states of myeloid immune cells, demonstrating functional consequences of the epigenetic edits.
  • Importantly, the methylation patterns persisted through cell division and lineage differentiation, indicating that epigenetic editing can produce heritable effects without altering the underlying DNA sequence.
  • The study also links these edits to changes in gene expression and cell fate dynamics, suggesting new ways to probe the role of epigenetic modifications in development and disease. 

Why Important

  • Novel epigenetic editing in primary human cells: It shows that targeted epigenetic editing — not just genetic editing — can be performed in clinically relevant human stem cells and lead to sustained, heritable effects through differentiation. 
  • Expands CRISPR utility beyond DNA sequence changes: Traditional CRISPR‑Cas9 alters DNA sequences; here, the technology is repurposed to edit epigenetic marks (DNA methylation) with long‑lasting biological consequences, opening new avenues for research and potential therapies. 
  • Translational relevance: By altering how genes are regulated without changing the genetic code, this approach could lead to new strategies for modulating cell functions in diseases where epigenetic dysregulation plays a role, such as blood disorders and cancer. 

Summary

This PNAS paper showed that CRISPR‑based epigenetic editing can be heritable in human hematopoietic cells and influence their biological behavior, representing a major advance in our ability to rewrite gene regulation in human cells without altering DNA sequence — a powerful new tool in biotechnology and potential therapeutic development.

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