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2021.12.13 Monday

A Close Look into the Regulation of CCL17―A Gene Involved in Hyperimmune Diseases

New insight into a key protein could lead to novel treatments for diseases such as contact dermatitis and asthma

The CCL17/TARC chemokine is involved in many immune-mediated diseases, and is a well-known biomarker of atopic dermatitis. However, the proteins that regulate CCL17 expression are not clear. Recently, scientists from Japan conducted experiments on cultures of dendritic cells focusing on PU.1, a key protein regulating gene expression in immune cells. Further experiments on mice showed that externally regulating PU.1 can alleviate certain asthma symptoms, hinting at potential therapeutic targets for hyperimmune diseases.

Allergies and many other types of immune system-related diseases originate from an interplay of complex chemical pathways that affect cell behavior, distribution, and development. One prominent example is the CCL17/TARC chemokine, a protein that contributes to allergy by attracting certain types of white blood cells, such as T cells and eosinophils. Despite the important and proven roles of CCL17/TARC in allergic diseases like contact dermatitis, not much is known about the transcription factors (proteins that regulate gene expression) involved in regulating the expression of the CCL17 gene.

To address this knowledge gap, a team of scientists from Japan conducted a detailed study, the results of which were published in Allergy, focusing on PU.1, a transcription factor known to regulate gene expression in various types of immune cells. Prof. Chiharu Nishiyama from Tokyo University of Science (TUS), who headed the study, explains why they targeted this specific protein: "A long time ago, we discovered that forced expression of PU.1 in certain types of blood cell lineages causes them to change into dendritic cells. Since then, I have developed a deep interest in the fact that PU.1 is a master transcription factor that regulates dendritic cell differentiation and gene expression."

The team conducted a series of detailed experiments to clarify, at the molecular level, the relationship that exists between CCL17, PU.1, and other associated transcription factors and promoters. They relied on small interfering RNAs (siRNAs), or short chains of nucleotides that interrupt the translation process (making proteins from a copied DNA segment into RNA) of a target protein with great precision, for their study. After targeting PU.1 with siRNAs in dendritic cell cultures, they observed a decrease in expression not only for PU.1 and CCL17 but also IRF4 and IRF8, two partner molecules of PU.1.

Through further experiments in cell cultures followed by computational analysis, the team found that IRF4 and PU.1 work together synergistically to activate the transcription (copying of a DNA segment into RNA) of TARC in dendritic cells through the regulatory region of the CCL17 gene. Although this regulatory mechanism appears to be preserved across mammals, the scientists also discovered that the human CCL17 gene contains an additional promoter that is activated in keratinocytes, the most common type of cell found in the outermost layer of our skin.

Finally, the scientists tested the effects of PU.1 suppression in vivo using an asthmatic mouse as a model. They found that a simple intranasal administration of PU.1 siRNA helped reduce TARC secretion and the associated infiltration of white blood cells into the bronchioles, effectively reducing the extent of inflammation in the lungs.

These results highlight the importance of PU.1 in inflammatory processes and immune diseases and could pave the way to novel treatments. "I find it encouraging that we were able to report both basic research on genes as well as an applied approach that could lead to treatment for hyperimmune responses, such as contact hypersensitivity and asthma," comments Prof. Nishiyama.

Hopefully, further research would help clarify the regulatory and transcriptional pathways of CCL17 even more, leading to a more comprehensive understanding of the complex panorama of immune diseases.

Reference
Authors  : Naoto Ito1, Fumiya Sakata1, Masakazu Hachisu1, Kazuki Nagata1, Tomoka Ito1, Kurumi Nomura1, Masanori Nagaoka1, Keito Inaba1, Mutsuko Hara2, Nobuhiro Nakano2, Tadaaki Nakajima1, Takuya Yashiro1, and Chiharu Nishiyama1
Title of original paper  : The Ccl17 gene encoding TARC is synergistically transactivated by PU.1 and IRF4 driven by the mammalian common promoter in dendritic cells
Journal  : Allergy
DOI  : 10.1111/all.15184
Affiliations  : 1Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science. 2Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine.

About The Tokyo University of Science

Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan's development in science through inculcating the love for science in researchers, technicians, and educators.

With a mission of "Creating science and technology for the harmonious development of nature, human beings, and society", TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today's most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.

■Tokyo University of Science(About TUS) : https://www.tus.ac.jp/en/about/
■Research List: https://www.tus.ac.jp/en/news/03/
About Professor Chiharu Nishiyama from Tokyo University of Science

Professor Chiharu Nishiyama is affiliated with Faculty of Advanced Engineering, Department of Biological Science and Technology. She received her postgraduate degree in 1990 from the Department of Agricultural Chemistry at University of Tokyo Graduate School, followed by a PhD from the University of Tokyo. Her areas of research interest include applied biochemistry including immunology, allergy, molecular biology, transcription factors, and cell development. She has published around 130 research papers in international journals. She also received the prestigious JSBBA Award for Young Scientists in 2005, JSA Award for Young Scientists in 2005, and JAFI Award in 2019.
https://www.tus.ac.jp/en/fac/p/index.php?6821
https://www.rs.tus.ac.jp/chinishi/

About Junior Associate Professor Masakazu Hachisu from Tokyo University of Science

https://www.tus.ac.jp/en/fac/p/index.php?6B19

Funding information

This study was supported by a Grant-in-Aid for Scientific Research (B) (20H02939 Grant-in-Aid for Scientific Research (C) (21K05297 and 19K05884), a Research Fellowship for Young Scientists (DC2) and Grant-in-Aid for JSPS Fellows 21J12113, a Tokyo University of Science Grant for President's Research Promotion, the MEXT-Supported Program for the Strategic Research Foundation at Private Universities (Translational Research Center, Tokyo University of Science), the Tojuro Iijima Foundation for Food Science and Technology, a Research Grant from the Mishima Kaiun Memorial Foundation, and a Research Grant from Takeda Science Foundation.

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