Wang Yingxiang's team revealed the molecular mechanism of meiosis heterochromatin concentration

Wang Yingxiang's team revealed the molecular mechanism of meiosis heterochromatin concentration

Meiosis is a necessary life process for the sexual reproduction of eukaryotes, which through homologous chromosome recombination, free combination of non-homologous chromosomes and two divisions finally form haploid gametes, which ensures the relative stability of genetic material and increases the differences between individuals, so that species can reproduce and evolve
.
Meiosis is closely related
to crop fertility and yield, as well as human reproductive health.

Chromosomes consist of relatively loose autochromatin and highly concentrated heterochromatin
.
Relative to the relative enrichment of chromatin genes, repeat sequences and transposons of heterochromatin regions are relatively enriched
.
In meiosis, the normochromin region is the hot zone where recombination occurs, and heterochromatin is the cold zone
where recombination occurs.
In addition, normal heterochromatin formation is essential
to inhibit transposon activity, maintain genome stability, and ensure proper separation of chromosomes.
At present, the mechanism of heterochromatin formation and concentration in the process of mitosis has been recognized, but in meiosis, it is only understood that heterochromatin regions inhibit the occurrence of recombination and promote early homologous chromosome pairing, and the dynamic changes and functional properties of chromatin are different from the mitosis process, but the formation and concentration mechanism of heterochromatin in meiosis is unclear
.

On October 17, 2022, the team of Wang Yingxiang of Fudan University published a paper entitled " DNA Polymerase Epsilon Binds Histone H3.
1-H4 and Recruits MORC1 to Mediate Meiotic Heterochromatin Condensation
".
The study revealed the specific recognition of histone dimers by the DNA polymerase epsilon (POL ε) during plant meiosis H3.
1-H4 and recruits the molecular mechanism
by which the MORC1 protein controls heterochromatin formation.

Previous studies have found that POL2A, the largest subunit of DNA leading chain synthetase POL ε, has important functions in meiosis recombination (Huang et al.
, PNAS, 2015).
But the underlying molecular mechanisms are unclear
.
Recent studies have revealed the molecular mechanism by which POL2A inhibits gene transcription in the recombinant hot zone of chromatin by recruiting SUVH2/9 Wang et al.
, PNAS, 2022）
。 Interestingly, this gene mutation also affected the normal concentration
of heterochromatin in meiosis.
In this study, the investigators used cytological molecular markers to prove abnormal chromatin structure and modification in the POL2A mutant; To investigate how POL2A, a DNA replication factor, regulates heterochromatin structure, the researchers found that the N-terminus of POL2A can concentrate proteins through interactive screening ATPase MORC1 interacts and co-influences meiosis heterochromatin structure and modification, suggesting that they may be in the same genetic pathway; At the same time, the researchers also found that the localization of MORC1 on the chromosome during meiosis is dependent on POL2A, suggesting that POL2A is responsible for recruiting MORC1 during meiosis to heterochromatin involved in the concentration process
.

As a DNA polymerase, how does POL ε recruit MORC1 to the heterochromatin region? The investigators further found that the C-terminal zinc finger (ZF) domain of POL2A can specifically bind histones Tetramers of H3.
1-H4 and conserved
in different species.
Previous studies have found that the histone variant H3.
1 is normally enriched in heterochromatin, is essential for both heterochromatin formation and modification, and is specifically loaded onto chromosomes
via the CAF1 complex during DNA replication.
Transgenic genetic analysis showed that the ZF domain of POL2A is crucial for the localization of heterochromatin structure and H3.
1.
And interestingly, the mutation of two special amino acids A31 and S87 on the histone variant H3.
1 affects the interaction with POL2A-ZF.
And it also affects its own positioning
in the plant.
These results suggest that POL2A, by specifically recognizing H3.
1-H4, may be directly involved in DNA replication-conjugated H3.
1 nucleosome assembly and localize to heterochromatin regions
。

Figure 1.
POL ε regulate meiosis heterochromatin formation models

In summary, this study revealed the molecular mechanism of the all-rounder DNA polymerase POLε involved in the formation of meiosis heterochromatin, proving that it is involved in DNA synthesis at the same time.
It is possible to identify and participate in the assembly of histone H3.
1-H4 to form nucleosomes by the C-terminus of the catalytic subunit POL2A; After replication is completed, POL2A continues to stay in the heterochromatin region by binding to H3.
1-H4 and recruits the concentrated complex MORC1/6 at the N-terminus, The result is the formation of heterochromatin with highly concentrated meiosis (Figure 1).

Since POL ε is highly conserved in different organisms, the researchers speculate that the mechanism of its role in meiosis is relatively conserved
in eukaryotes.

Finally, it is worth mentioning that the two articles published by Wang Yingxiang's team in PNAS have comprehensively revealed that the DNA polymerase POLε enters meiosis after chromosome replication, which binds to the new function of meiotic normin and heterochromatin regions, respectively
。 Wang Cong, a postdoctoral fellow at the School of Life Sciences, Fudan University, is the first author of the two articles, and Huang Jiyue, a postdoctoral fellow at the University of North Carolina at Chapel Hill and a professor at South China Agricultural University Professor Yingxiang Wang, Fudan University/South China Agricultural University/Lingnan Modern Agricultural Biology and Technology Guangdong Laboratory of Modern Agricultural Biology and Technology, University of North Carolina at Chapel Hill Gregory Copenhaver and Professor Ma Hong of the Department of Biology at the University of Pennsylvania are co-corresponding authors.

Professor Dong Aiwu of Fudan University and researcher Jiang Danhua of the University of Chinese Academy of Sciences/Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences provided guidance and assistance, and Fudan University graduate students Li Yingping, Zhang Jun, He Chengpeng and Li Tianyang also participated in the work
.
The work was supported by grants
from the National Natural Science Foundation of China, Fudan University, the China Postdoctoral Fund, and the University of North Carolina.

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