Transcriptional activation of endogenous Oct4 via the CRISPR/dCas9 activator ameliorates Hutchinson-Gilford progeria syndrome in mice

Junyeop Kim, Yerim Hwang, Sumin Kim, Yujung Chang, Yunkyung Kim, Youngeun Kwon, Jongpil Kim

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Partial cellular reprogramming via transient expression of Oct4, Sox2, Klf4, and c-Myc induces rejuvenation and reduces aged-cell phenotypes. In this study, we found that transcriptional activation of the endogenous Oct4 gene by using the CRISPR/dCas9 activator system can efficiently ameliorate hallmarks of aging in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS). We observed that the dCas9-Oct4 activator induced epigenetic remodeling, as evidenced by increased H3K9me3 and decreased H4K20me3 levels, without tumorization. Moreover, the progerin accumulation in HGPS aorta was significantly suppressed by the dCas9 activator-mediated Oct4 induction. Importantly, CRISPR/dCas9-activated Oct4 expression rescued the HGPS-associated vascular pathological features and lifespan shortening in the mouse model. These results suggest that partial rejuvenation via CRISPR/dCas9-mediated Oct4 activation can be used as a novel strategy in treating geriatric diseases.

Original languageEnglish
Article numbere13825
JournalAging Cell
Volume22
Issue number6
DOIs
StatePublished - Jun 2023

Keywords

  • CRISPR/dCas9
  • Hutchinson-Gilford progeria syndrome
  • Oct4
  • aging
  • rejuvenation

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