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SUMMARY:Physiological roles of aberrant DNA methylation in vitro and in vi
 vo - Gabriella Ficz
DTSTART:20231128T120000Z
DTEND:20231128T130000Z
UID:TALK205264@talks.cam.ac.uk
CONTACT:90994
DESCRIPTION:Aging is associated with an abnormal increase of DNA methylati
 on in human gene promoters\, including in bone marrow stem cells. DNA meth
 ylation 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 abe
 rrant DNA methylation on the CDKN2A locus in human primary epithelial cell
 s\, 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 affe
 cts hematopoiesis in vivo. We edited the CDKN2B (p15) promoter and ARF (p1
 4) using dCas9-3A3L and observed DNA methylation spreading beyond the gRNA
  location. We find that despite a transient delivery system\, DNA methylat
 ion is maintained during myeloid differentiation in vitro\, and hypermethy
 lation of the p15 promoter reduces gene expression. In vivo\, edited human
  HSPCs can engraft the bone marrow of mice and targeted DNA methylation is
  maintained in HSPCs long term. Moreover\, epigenetic changes are conserve
 d and inherited in both myeloid and lymphoid lineages. Although the propor
 tion of myeloid (CD33+) and lymphoid (CD19+) cells is unaffected\, monocyt
 e (CD14+) populations decreased and granulocytes (CD66b+) increased in mic
 e engrafted with p15 hypermethylated HSPCs. Monocytes derived from p15 hyp
 ermethylated HSPCs appear to be activated and show increased inflammatory 
 transcriptional programs. We believe these findings have clinical relevanc
 e since we found p15 promoter methylation in the peripheral blood of patie
 nts with clonal hematopoiesis. Our study shows DNA methylation can be targ
 eted and maintained in human HSPCs and demonstrated functional relevance o
 f aberrant DNA methylation on the p15 locus. As such\, other ageing associ
 ated aberrant DNA methylation may impact hematopoiesis in vivo. 
LOCATION:Jean Thomas Lecture theatre\, Sanger Building\, Tennis Court Road
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