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Role of the PRC2-Six1-miR-25 signaling axis in heart failure..pdf (2.73 MB)

Role of the PRC2-Six1-miR-25 signaling axis in heart failure.

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journal contribution
posted on 2019-03-06, 15:11 authored by Jae Gyun OhJae Gyun Oh, Seung Pil Jang, Jimeen Yoo, Min-Ah Lee, Seung Hee Lee, Taejoong lim, eden jeong, changwon khochangwon kho, Hyun Kook, Roger J. Hajjar, Woo Jin Park, Dongtak Jeong
The reduced expression of cardiac sarco-endoplasmic reticulum Ca2+ ATPase (SERCA2a) is a hallmark of heart
failure. We previously showed that miR-25 is a crucial transcriptional regulator of SERCA2a in the heart.
However, the precise mechanism of cardiac miR-25 regulation is largely unknown. Literatures suggested that
miR-25 is regulated by the transcriptional co-factor, sine oculis homeobox homolog 1 (Six1), which in turn is
epigenetically regulated by polycomb repressive complex 2 (PRC 2) in cardiac progenitor cells. Therefore, we
aimed to investigate whether Six1 and PRC2 are indeed involved in the regulation of the miR-25 level in the
setting of heart failure. Six1 was up-regulated in the failing hearts of humans and mice. Overexpression of Six1
led to adverse cardiac remodeling, whereas knock-down of Six1 attenuated pressure overload-induced cardiac
dysfunction. The adverse effects of Six1 were ameliorated by knock-down of miR-25. The epigenetic repression
on the Six1 promoter by PRC2 was significantly reduced in failing hearts. Epigenetic repression of Six1 is relieved
through a reduction of PRC2 activity in heart failure. Six1 up-regulates miR-25, which is followed by
reduction of cardiac SERCA2a expression. Collectively, these data showed that the PRC2-Six1-miR-25 signaling
axis is involved in heart failure. Our finding introduces new insight into potential treatments of heart failure.


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    American Heart Association



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