Highly rigid H3.1/H3.2–H3K9me3 domains set a barrier for cell fate reprogramming in trophoblast stem cells

Author:

Hada Masashi,Miura Hisashi,Tanigawa Akie,Matoba ShogoORCID,Inoue Kimiko,Ogonuki Narumi,Hirose Michiko,Watanabe Naomi,Nakato RyuichiroORCID,Fujiki Katsunori,Hasegawa Ayumi,Sakashita Akihiko,Okae Hiroaki,Miura Kento,Shikata Daiki,Arima Takahiro,Shirahige Katsuhiko,Hiratani Ichiro,Ogura Atsuo

Abstract

The placenta is a highly evolved, specialized organ in mammals. It differs from other organs in that it functions only for fetal maintenance during gestation. Therefore, there must be intrinsic mechanisms that guarantee its unique functions. To address this question, we comprehensively analyzed epigenomic features of mouse trophoblast stem cells (TSCs). Our genome-wide, high-throughput analyses revealed that the TSC genome contains large-scale (>1-Mb) rigid heterochromatin architectures with a high degree of histone H3.1/3.2–H3K9me3 accumulation, which we termed TSC-defined highly heterochromatinized domains (THDs). Importantly, depletion of THDs by knockdown of CAF1, an H3.1/3.2 chaperone, resulted in down-regulation of TSC markers, such as Cdx2 and Elf5, and up-regulation of the pluripotent marker Oct3/4, indicating that THDs maintain the trophoblastic nature of TSCs. Furthermore, our nuclear transfer technique revealed that THDs are highly resistant to genomic reprogramming. However, when H3K9me3 was removed, the TSC genome was fully reprogrammed, giving rise to the first TSC cloned offspring. Interestingly, THD-like domains are also present in mouse and human placental cells in vivo, but not in other cell types. Thus, THDs are genomic architectures uniquely developed in placental lineage cells, which serve to protect them from fate reprogramming to stably maintain placental function.

Funder

Japan Society of the Promotion of Science

Grant-in-Aid for JSPS Fellows

Grant-in-Aid for Early-Career Scientists

Ministry of Education, Culture, Sports, Science, and Technology

Grants-in-Aid for

Scientific Research in Innovative Areas

JST CREST

RIKEN Genome Building

Project

All-RIKEN

Publisher

Cold Spring Harbor Laboratory

Subject

Developmental Biology,Genetics

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