A new mechanism of regulation of circular RNA in childhood asthma

Asthma is the most common chronic respiratory disease in children, in recent years, its incidence has shown a rapid upward trend, the incidence of childhood asthma in China from 1990 to 2010 increased from 1.
09% to 3.
02%, 20 years increased by 2.
8 times
.
At present, the incidence of asthma in children in Shanghai has exceeded 8%, becoming the city with the highest incidence in China, which seriously affects the growth and development of children and their physical and mental health
.
Asthma is an immuno-inflammatory disease
caused by the interaction of genetic, environmental and epigenetic factors.
Epigenetics is a stable genetic phenotype produced by chromatin changes that do not depend on DNA sequence changes, including DNA methylation, histone modifications, RNA modifications, non-coding RNAs, etc
.

Non-coding RNA refers to RNA that cannot code for proteins, including miRNAs, long non-coding RNAs (LncRNAs), and ring RNAs (circRNAs
).
Previously thought of noncoding RNAs as a group of junk RNAs, recent studies have found that noncoding has important immunomodulatory functions
.
In recent years, Zhou Yufeng's research group has conducted a lot of research work on epigenetic factors and the regulatory role of non-coding RNAs in asthma and allergic diseases, and has achieved a series of results: the discovery of miRNA (miR-511-3p) (JACI, 2018, PMID: 28629744), long-chain non-coding RNA (LncRNA PTPRE-AS1) and histone methylation modifications (Science Advances, 2019, PMID: 31844669), the role and mechanism
of long non-coding RNA Lnc-BAZ2B and acetylated modifications (JACI, 2021, PMID: 32712329) and cyclic RNA Hsa_circ_0004287 and m6A modifications (JACI, 2022, PMID:34953789) in the diagnosis and treatment of asthma and allergic diseases.

On September 14, 2022, the team of Zhou Yufeng of our hospital and the research group of Qian Liling of the Children's Hospital of Fudan University published an article entitled circS100A11 enhances M2a macrophage activation and lunginflammation in children with asthma in the journal Allergy, a top journal in the field of allergy in the world.
The role and mechanism
of circular RNA in regulating M2 macrophage activation and allergic asthma in children were revealed.

The study found that there were 372 differently expressed ring RNAs in peripheral blood mononuclear cells in childhood asthma patients, of which the expression of circS100A11 was significantly increased
.
Functional studies have found that circS100A11 can promote the activation of M2 macrophages: knocking down the expression of circS100A11 in macrophages can significantly inhibit the expression of CD206, CD209 of M2 macrophage-related genes.
Overexpression of circS100A11 promotes the expression
of genes related to the activation of M2-type macrophages.
In terms of mechanism research, it was found that circS100A11 can compete to bind to cycle-related protein 1 (CAPRIN1), lift the inhibition of CAPRIN1 on the protein translation of S100A11, and then promote the protein expression
of S100A11 。 S100A11 can compete to bind to nucleolin (nucleolin) to promote the release of transcription factor SP3, and free SP3 can bind to the upstream of STAT6 transcription starting point -1300bp, promote signaling and transcriptional activation protein 6 (STAT6) to promote macrophage M2 activation, enhance the expression
of Th2 cell chemokines CCL17 and CCL22 。 Overexpression of circS100A11 in vivo enhances asthma symptoms in mice with allergic asthma induced by cockroach extract; Knocking down S100a11 reduced asthma symptoms
in asthmatic mice.
Previous genome-wide association analysis (GWAS) studies have shown that S100a11 is associated with asthma, but the mechanism is unclear, and this study also elucidated for the first time the molecular mechanism
by which S100a11 is involved in the occurrence and development of asthma by regulating M2 macrophage activation.

In summary, the study suggests that circS100A11 can promote macrophage M2 activation and worsen asthma
.
circS100A11 promotes the expression
of S100A11 through competition in conjunction with CAPRIN1.
S100A11 promotes the binding of SP3 to the STAT6 promoter region by competing to bind the transcription factor SP3 released by nucleolin, thereby promoting the expression of STAT6 and macrophage M2 activation
.
In vivo and in vitro experiments have shown that circS100A11 and S100A11 play an important role in the process of aggravating asthma disease and can become potential diagnostic and therapeutic targets for
children with asthma.

It is reported that Liang Qiuyan and Fu Jinrong, doctoral students of the Children's Hospital Affiliated to Fudan University, are the co-first authors of the article; Zhou Yufeng, a researcher at the Pediatric Hospital/Institute of Biomedical Sciences of Fudan University, and Qian Liling, a researcher at the Children's Hospital of Fudan University, are co-corresponding authors
of the article.

Original link: https://onlinelibrary.
wiley.
com/doi/10.
1111/all.
15515

DOI:https://doi.
org/10.
1111/all.
15515