Tet1 regulates epigenetic remodeling of the pericentromeric heterochromatin and chromocenter organization in DNA hypomethylated cells.

Yota Hagihara,Satoshi Asada,Takahiro Maeda,Toru Nakano,Shinpei Yamaguchi,Beth A Sullivan

doi:10.1371/journal.pgen.1009646

Abstract

Pericentromeric heterochromatin (PCH), the constitutive heterochromatin of pericentromeric regions, plays crucial roles in various cellular events, such as cell division and DNA replication. PCH forms chromocenters in the interphase nucleus, and chromocenters cluster at the prophase of meiosis. Chromocenter clustering has been reported to be critical for the appropriate progression of meiosis. However, the molecular mechanisms underlying chromocenter clustering remain elusive. In this study, we found that global DNA hypomethylation, 5hmC enrichment in PCH, and chromocenter clustering of Dnmt1-KO ESCs were similar to those of the female meiotic germ cells. Tet1 is essential for the deposition of 5hmC and facultative histone marks of H3K27me3 and H2AK119ub at PCH, as well as chromocenter clustering. RING1B, one of the core components of PRC1, is recruited to PCH by TET1, and PRC1 plays a critical role in chromocenter clustering. In addition, the rearrangement of the chromocenter under DNA hypomethylated condition was mediated by liquid-liquid phase separation. Thus, we demonstrated a novel role of Tet1 in chromocenter rearrangement in DNA hypomethylated cells.

Highlights

The chromosomal region around the centromere, which is named pericentromere, is ~5% in mice
The DAPI-dense chromocenter in the nucleus consists of accumulated pericentromeric heterochromatin
We demonstrated that the DNA demethylation-related factor, TET1 plays a critical role in the chromosome clustering by recruiting Polycomb factors

Summary

Introduction

The chromosomal region around the centromere, which is named pericentromere, is ~5% in mice. The pericentromeric region of mouse cells is mainly comprised of a 234 bp long AT-rich repetitive sequence, called major satellite repeats. This region forms constitutive heterochromatin harboring high levels of trimethylation of histone H3 lysine 9 (H3K9me3) and DNA methylation at the C-5 position of cytosine (5mC) [1]. Chromocenter clustering is observed in germ cells at the meiotic prophase and plays an important role in subsequent meiotic processes, including centromere clustering, homologous chromosome pairing, and synapsis formation [5]. Previous studies have mainly focused on wild-type ESCs under regular culture conditions and failed to link the clustering mechanism to changes in the epigenetic state

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Conclusion