RT Journal Article
SR Electronic
T1 Acidic microenvironment shaped by lactate accumulation promotes pluripotency through multiple mechanisms
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 282475
DO 10.1101/282475
A1 Wen-Ting Guo
A1 Shao-Hua Wang
A1 Xiao-Shan Zhang
A1 Ming Shi
A1 Jing Hao
A1 Xi-Wen Wang
A1 Kai-Li Gu
A1 Fei-Fei Duan
A1 Ying Yan
A1 Xi Yang
A1 Chao Zhang
A1 Le-Qi Liao
A1 Yangming Wang
YR 2018
UL http://biorxiv.org/content/early/2018/03/15/282475.abstract
AB Enhanced glycolysis is a distinct feature associated with numerous stem cells and cancer cells. However, little is known about its regulatory roles in gene expression and cell fate determination. Here we show that acidic environment shaped by lactate accumulation promotes the self-renewal and pluripotency of both mouse and human embryonic stem cells (ESCs). Mechanistically, acidic pH reduces the tri-methylation of H3K27 globally at transcriptional start sites to partially prevent ESC differentiation. In addition, acidic pH stabilizes a large number of mRNAs including pluripotency genes. Furthermore, we found that AGO1 protein is downregulated at acidic conditions, leading to the de-repression of a subset of microRNA targets in low-pH treated ESCs. Altogether, our study provides insights into mechanisms whereby acidic microenvironment produced by enhanced glycolysis regulates gene expression to determine cell fate and has broad implications in the fields of regenerative medicine and cancer biology.