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  • SETDB1-Mediated Cell Fate Transition between 2C-Like and Pluripotent States.

SETDB1-Mediated Cell Fate Transition between 2C-Like and Pluripotent States.

Cell reports (2020-01-09)
Kaixin Wu, He Liu, Yaofeng Wang, Jiangping He, Shuyang Xu, Yaping Chen, Junqi Kuang, Jiadong Liu, Lin Guo, Dongwei Li, Ruona Shi, Li Shen, Yangming Wang, Xiaofei Zhang, Jie Wang, Duanqing Pei, Jiekai Chen
ABSTRACT

Known as a histone H3K9 methyltransferase, SETDB1 is essential for embryonic development and pluripotent inner cell mass (ICM) establishment. However, its function in pluripotency regulation remains elusive. In this study, we find that under the "ground state" of pluripotency with two inhibitors (2i) of the MEK and GSK3 pathways, Setdb1-knockout fails to induce trophectoderm (TE) differentiation as in serum/LIF (SL), indicating that TE fate restriction is not the direct target of SETDB1. In both conditions, Setdb1-knockout activates a group of genes targeted by SETDB1-mediated H3K9 methylation, including Dux. Notably, Dux is indispensable for the reactivation of 2C-like state genes upon Setdb1 deficiency, delineating the mechanistic role of SETDB1 in totipotency restriction. Furthermore, Setdb1-null ESCs maintain pluripotent marker (e.g., Nanog) expression in the 2i condition. This "ground state" Setdb1-null population undergoes rapid cell death by activating Ripk3 and, subsequently, RIPK1/RIPK3-dependent necroptosis. These results reveal the essential role of Setdb1 between totipotency and pluripotency transition.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Iodoacetamide, BioUltra
Sigma-Aldrich
ChIPAb+ Trimethyl-Histone H3 (Lys27) - ChIP Validated Antibody and Primer Set, from rabbit, purified by using Protein A
Supelco
Empore SPE Disks, matrix active group C18, diam. 47 mm, pk of 20
Sigma-Aldrich
Anti-Glyceraldehyde-3-Phosphate Dehydrogenase Antibody, clone 6C5, clone 6C5, Chemicon®, from mouse