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

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

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


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.

Original languageEnglish
Pages (from-to)84-102
Number of pages19
JournalGenes & development
Issue number1-2
Publication statusPublished - 2022 Jan 1


  • CAF1
  • H3.1/H3.2
  • H3K9me3
  • somatic cell nuclear transfer
  • trophoblast stem cell

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology


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