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2017 ; 144
(15
): 2748-2763
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Epigenetic resetting of human pluripotency
#MMPMID28765214
Guo G
; von Meyenn F
; Rostovskaya M
; Clarke J
; Dietmann S
; Baker D
; Sahakyan A
; Myers S
; Bertone P
; Reik W
; Plath K
; Smith A
Development
2017[Aug]; 144
(15
): 2748-2763
PMID28765214
show ga
Much attention has focussed on the conversion of human pluripotent stem cells
(PSCs) to a more naïve developmental status. Here we provide a method for
resetting via transient histone deacetylase inhibition. The protocol is effective
across multiple PSC lines and can proceed without karyotype change. Reset cells
can be expanded without feeders with a doubling time of around 24?h. WNT
inhibition stabilises the resetting process. The transcriptome of reset cells
diverges markedly from that of primed PSCs and shares features with human inner
cell mass (ICM). Reset cells activate expression of primate-specific transposable
elements. DNA methylation is globally reduced to a level equivalent to that in
the ICM and is non-random, with gain of methylation at specific loci. Methylation
imprints are mostly lost, however. Reset cells can be re-primed to undergo
tri-lineage differentiation and germline specification. In female reset cells,
appearance of biallelic X-linked gene transcription indicates reactivation of the
silenced X chromosome. On reconversion to primed status, XIST-induced silencing
restores monoallelic gene expression. The facile and robust conversion routine
with accompanying data resources will enable widespread utilisation,
interrogation, and refinement of candidate naïve cells.