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Inhibition of Human Y Chromosome Gene, SRY, Promotes Naïve State of Human Pluripotent Stem Cells
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posted on 2019-10-15, 18:34 authored by Sara Taleahmad, Mehdi Alikhani, Sepideh Mollamohammadi, Meisam Yousefi, Adeleh Taei, Seyedeh Nafiseh Hassani, Hossein Baharvand, Ghasem Hosseini SalekdehAlthough males and
females have a variety of sexually dimorphic
features related to hormonal effects, the genetic basis of dimorphism
relies on early embryo development. Two pluripotent states, naïve
and primed, emerge during early mammalian development. Identification
of signaling pathways that induce differences between these two states
can help to modulate conversion of primed cells to naïve cells.
Naïve cells have a shorter doubling time and longer survival
than their primed counterparts when passaged as single cells. In this
study, we sought to explore the role of Y chromosome genes on human
pluripotent stem cells (hPSCs) by investigating differential expressions
of the male-specific region of the Y chromosome (MSY) genes in primed
and naïve cells. Interestingly, we found that several MSY genes,
including SRY, showed higher expression levels in
primed compared to naïve human embryonic stem cells (hESCs).
We hypothesize that SRY prevents WNT/β-catenin
signaling by its interaction and inhibition of β-catenin activation
in the nucleus. Results of the loss-of-function approach conducted
by depletion of SRY indicated increased expressions
of pluripotency marker genes and alkaline phosphatase (ALP) activity
in the primed cells. SRY reduction was associated
with overexpression of WNT signaling target genes AXIN2, Brachury, TCF1, TBX2, and TBX3. We suggest that inhibition of SRY may result in activation of β-catenin and up-regulation
of the WNT signaling pathway, both of which are important to naïve
conversion.
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β- catenin activationdimorphic featurespluripotent statesHuman Pluripotent Stem CellsY chromosomemale-specific regionTCF 1pluripotency marker genesTBX 3TBX 2WNTSRY reductionβ- cateninloss-of-function approachY chromosome genesexpression levelsALPembryo developmentHuman Y Chromosome GenenaiMSY genestarget genes AXIN 2
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