Nature Genetics: Zhao Zhang/Lu Wang collaboration reveals a new role in reversing the colon in initiating the innate immune system to resist the invasion of exogenous viruses for a long time

Reverse locons are present in almost all eukaryotes and are extremely abundant
in the genome.
In humans, reversers make up up to 38%
of the genome.
After the activation of the reverse locon, the mRNA, proteins, and cDNA generated by reverse transcription are often detrimental to the body, potentially causing neurodegenerative diseases and cancer; In addition, reverse hoston transposation can cause DNA damage, genetic mutations, and genomic instability, not only leading to infertility but also driving the aging process
.
Therefore, researchers often believe that reversing locon activation is harmful to living
organisms.

Although the body has evolved a very fine regulatory mechanism to silence the activity of the reversal locus, it is still possible that the reversal locon can be activated at a specific time of life development or in a specific tissue, and the reversal locon activation under this physiological condition may give the species new physiological functions
.

On November 18, 2022, Zhang Zhao's laboratory in the Department of Pharmacology and Cancer Biology at Duke University and the laboratory of Wang Lu, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences (Center for Excellence in Molecular Cell Sciences), published a title in the journal Nature Genetics Recent research findings from Retrotransposon activation during Drosophila metamorphosis conditions adult antiviral
responses.

This study systematically established a tool to detect reverse locon transposability in somatic cells, and realized real-time tracking of reverse locus jumping events at the single-cell level, thereby revealing the important role of reversal locon activation in a specific developmental period that can activate the host's innate immune system to resist the invasion of foreign viruses for a long time, which provides a new direction
for studying the potential physiological function of reverse locus.

Zhang Zhao's group has long been working on the reversing of the capon jumping event, while studying the regulation of transposons in the reproductive system (Lu Wang et al.
, Cell, 2018; Sunjing Moon et al.
, Dev Cell, 2018), also working to explore its function
in somatic cells.

In this study, the research group first established a new system
for tracking transposon jumps in somatic cells using fruit flies as model animals.
Fruit flies are metamorphostically developing insects that go through the egg, larval, pupal and adult stages
.
During the pupal stage, fruit flies undergo metamorphosis, during which somatic tissue first degenerates and then rebuilds new somatic tissue
.
Interestingly, by tracking the activity and jumping events of MDG4 reversal locus during somatic tissue development in real time, this study found that MDG4 can specifically activate during the pupal phase and jump
only in newborn somatic cells.
The activation and transposition of the reversing locon at a specific time under this physiological condition suggests that MDG4 may have a specific function
in the development of fruit flies.

The innate immune system is a very critical natural barrier
against the invasion of foreign germs and thus the survival of the body.
The system is highly conserved in everything from yeast to plants and animals
.
Although the innate immune system does not produce an extremely efficient immune memory like the acquired immune system, studies have shown that the innate immune system shows better protection
against the next infection after being infected by one germ.

In this study, it was shown that mdg4-specific activation in the pupal phase can activate the host's innate immune system by activating the antiviral function of the NF-κB protein Relish, thereby protecting adult fruit flies against foreign viral invasion
.
Activation of mdg4 can promote the cleavage and nucleation effect of Relish, thereby enhancing the expression
of genes related to the innate immune system.
Interestingly, the study shows that only MDG4 activation in the pupal phase can activate the innate immune system to achieve long-term protection against foreign viruses
.

In conclusion, the study tracked the jumping events of reversal locons during somatic development in real time, and found that the host used the activation of reversal locons at a specific time to activate the innate immune system to protect itself against the invasion
of foreign viruses.
From an evolutionary point of view, though, the arms race between the host and the reverser has not stopped
.
However, in the exercise of certain physiological functions, the host successfully achieved "enemy for us"
for the reverse seater.
Under physiological conditions, the activation of the reversal locus not only does not have a harmful effect on the host, but will help the host to perform a specific function
.

This phenomenon is not only found in fruit flies, the study has found that there is also a specific period of reversal locon activation during the development of human embryos - 8 cells to blastocysts; The activation and function of this specific period of reversal of the locus may be evolutionarily conserved and deserves our in-depth study
.
And transposon research will surely be able to bring us more new "surprises"
in the near future.

Wang Lu and Lauren Tracy of Zhang Zhao's group are co-first authors, and Wang Lu and Zhang Zhao are co-corresponding authors of the paper, and the study was strongly supported
by Dr.
Su Weijia, Dr.
Yang Axe, Feng Yu from Wang Lu's group, and Dr.
Neal Silverman from the University of Massachusetts Medical School.

Zhao Zhang's laboratory (ZZ-Lab), which recently discovered that reversal locons produce a large amount of circular DNA during jumping (Fu Yang et al.
, bioRxiv, 2022), is now working to study the role of transposons and circular DNA in physiological and disease processes such as cancer, with a view to providing new ideas and targets for cancer research
.
Lu Wang's laboratory (established in May 2021) is actively exploring the new physiological functions of reversal colons and their regulatory networks
that are silenced during somatic development.
Both research groups are committed to the cultivation of team members, and sincerely invite sincere people to join and cooperate!

Paper link:

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