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2016 ; 16
(2
): 507-18
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Re-patterning of H3K27me3, H3K4me3 and DNA methylation during fibroblast
conversion into induced cardiomyocytes
#MMPMID26957038
Liu Z
; Chen O
; Zheng M
; Wang L
; Zhou Y
; Yin C
; Liu J
; Qian L
Stem Cell Res
2016[Mar]; 16
(2
): 507-18
PMID26957038
show ga
Direct conversion of fibroblasts into induced cardiomyocytes (iCMs) offers an
alternative strategy for cardiac disease modeling and regeneration. During iCM
reprogramming, the starting fibroblasts must overcome existing epigenetic
barriers to acquire the CM-like chromatin pattern. However, epigenetic dynamics
along this reprogramming process have not been studied. Here, we took advantage
of our recently generated polycistronic system and determined the dynamics of two
critical histone marks, H3K27me3 and H3K4me3, in parallel with gene expression at
a set of carefully selected cardiac and fibroblast loci during iCM reprogramming.
We observed reduced H3K27me3 and increased H3K4me3 at cardiac promoters as early
as day 3, paralleled by a rapid significant increase in their mRNA expression. In
contrast, H3K27me3 at loci encoding fibroblast marker genes did not increase
until day 10 and H3K4me3 progressively decreased along the reprogramming process;
these changes were accompanied by a gradual decrease in the mRNA expression of
fibroblast marker genes. Further analyses of fibroblast-enriched transcription
factors revealed a similarly late deposition of H3K27me3 and decreased mRNA
expression of Sox9, Twist1 and Twist2, three important players in
epithelial-mesenchymal transition. Our data suggest early rapid activation of the
cardiac program and later progressive suppression of fibroblast fate at both
epigenetic and transcriptional levels. Additionally, we determined the DNA
methylation states of representative cardiac promoters and found that not every
single CpG was equally demethylated during early stages of iCM reprogramming.
Rather, there are specific CpGs, whose demethylation states correlated tightly
with transcription activation, that we propose are the major contributing CpGs.
Our work thus reveals a differential re-patterning of H3K27me3, H3K4me3 at
cardiac and fibroblast loci during iCM reprogramming and could provide future
genome-wide epigenetic studies with important guidance such as the appropriate
time window and loci to be utilized as positive and negative controls.
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