Physiological roles of aberrant DNA methylation in vitro and in vivo

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• Gabriella Ficz
• Tuesday 28 November 2023, 12:00-13:00
• Jean Thomas Lecture theatre, Sanger Building, Tennis Court Road.

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Aging is associated with an abnormal increase of DNA methylation in human gene promoters, including in bone marrow stem cells. DNA methylation patterns are further perturbed in hematological malignancies such as acute myeloid leukemia (AML) but the physiological significance of such epigenetic changes is unknown. Previously, we have demonstrated that aberrant DNA methylation on the CDKN2A locus in human primary epithelial cells, which we obtained from healthy women undergoing mammoplasty, resulted in a physiological change and cells proliferated well beyond the Hayflick limit, exhibiting other cancer-like hallmarks. Using epigenetic editing of human stem/progenitor cells (HSPCs), we show that p15 methylation affects hematopoiesis in vivo. We edited the CDKN2B (p15) promoter and ARF (p14) using dCas9-3A3L and observed DNA methylation spreading beyond the gRNA location. We find that despite a transient delivery system, DNA methylation is maintained during myeloid differentiation in vitro, and hypermethylation of the p15 promoter reduces gene expression. In vivo, edited human HSP Cs can engraft the bone marrow of mice and targeted DNA methylation is maintained in HSP Cs long term. Moreover, epigenetic changes are conserved and inherited in both myeloid and lymphoid lineages. Although the proportion of myeloid (CD33+) and lymphoid (CD19+) cells is unaffected, monocyte (CD14+) populations decreased and granulocytes (CD66b+) increased in mice engrafted with p15 hypermethylated HSP Cs. Monocytes derived from p15 hypermethylated HSP Cs appear to be activated and show increased inflammatory transcriptional programs. We believe these findings have clinical relevance since we found p15 promoter methylation in the peripheral blood of patients with clonal hematopoiesis. Our study shows DNA methylation can be targeted and maintained in human HSP Cs and demonstrated functional relevance of aberrant DNA methylation on the p15 locus. As such, other ageing associated aberrant DNA methylation may impact hematopoiesis in vivo.

This talk is part of the Department of Biochemistry - Tea Club Seminars series.

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