Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jul 1:16:877802.
doi: 10.3389/fnins.2022.877802. eCollection 2022.

Multiplexed Visualization Method to Explore Complete Targeting Regulatory Relationships Among Circadian Genes for Insomnia Treatment

Tao Li  1 , Zhenyu Liu  2 , Yitong Wang  3 , Dongshi Zuo  2 , Shenyuan Wang  1 , Haitao Ju  4 , Shichao Wang  5 , Yanping Xing  1 , Yu Ling  1 , Chunxia Liu  1 , Yanru Zhang  1 , Huanmin Zhou  1 , Jun Yin  1 , Junwei Cao  1 , Jing Gao  2
Affiliations

Multiplexed Visualization Method to Explore Complete Targeting Regulatory Relationships Among Circadian Genes for Insomnia Treatment

Tao Li et al. Front Neurosci. .

Abstract

Understanding the complete map of melatonin synthesis, the information transfer network among circadian genes in pineal gland, promises to resolve outstanding issues in endocrine systems and improve the clinical diagnosis and treatment level of insomnia, immune disease and hysterical depression. Currently, some landmark studies have revealed some genes that regulate circadian rhythm associated with melatonin synthesis. However, these studies don't give a complete map of melatonin synthesis, as transfer information among circadian genes in pineal gland is lost. New biotechnology, integrates dynamic sequential omics and multiplexed imaging method, has been used to visualize the complete process of melatonin synthesis. It is found that there are two extremely significant information transfer processes involved in melatonin synthesis. In the first stage, as the light intensity decreased, melatonin synthesis mechanism has started, which is embodied in circadian genes, Rel, Polr2A, Mafk, and Srbf1 become active. In the second stage, circadian genes Hif1a, Bach1, Clock, E2f6, and Per2 are regulated simultaneously by four genes, Rel, Polr2A, Mafk, and Srbf1 and contribute genetic information to Aanat. The expeditious growth in this technique offer reference for an overall understanding of gene-to-gene regulatory relationship among circadian genes in pineal gland. In the study, dynamic sequential omics and the analysis process well provide the current state and future perspectives to better diagnose and cure diseases associated with melatonin synthesis disorder.

Keywords: circadian genes; dynamic sequential omics; insomnia; melatonin synthesis; transfer information; visualization method.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The technology strategy for experimental protocols, data analysis methods, and visualization strategies.
Figure 2
Figure 2
The expression trend of 24 genes related to pineal circadian rhythm regulation.
Figure 3
Figure 3
The targeting relationship between 24 circadian genes.
Figure 4
Figure 4
The complete information transfer network among 24 rhythmic genes (A) The transfer information network among 24 rhythm genes for 480 dynamic timing samples (B) The column represents the information transfer network among 24 rhythm genes (7:03) can be split into a series of information transfer networks for each rhythm gene to the other 23 rhythm genes (C) The horizontal represents the time-dependent relationship for rhythm gene (Zmiz1) to the other 23 rhythm genes. (D) A flow graph represents the time-dependent variation of one-to-many relationship (gene Atf1 to the other 23 circadian genes). The red color blocks, indicating that the central gene significantly regulate other genes (P value < 0.05). The blue color blocks, indicating that the central gene is significantly regulated by other genes (P value < 0.05).
Figure 5
Figure 5
The time-dependent variation of transfer information among 24 circadian genes in 24 h. (A) The first extremely significant information transfer process occurs in 14:00–16:00. (B) The second extremely significant information transfer process occurs in 18:00–20:00.
Figure 6
Figure 6
The regulatory mechanism of first extremely significant information transfer process in 14:00-16:00. (A) The time-dependent variation of transfer information among 24 circadian genes in 14:00–16:00. (B) The complete regulatory relationship among 24 circadian genes in 14:00–16:00. (C) The target genes regulated by four 4 promoter genes, Rel, Polr2A, Mafk, and Srbf1. (D) The rate-limiting gene Aanat is activated by E2f6 in 14:00–16:00. (E) The main mechanism for information transfer process in 14:00–16:00, E2f6 is regulated simultaneously by 4 promoter genes, and contributes genetic information to Aanat. (F) The targeting regulatory relations between promoter genes and Aanat in 14:00–16:00.
Figure 7
Figure 7
The regulatory mechanism of second extremely significant information transfer process in 18:00–20:00. (A) The time-dependent variation of transfer information among 24 circadian genes in 18:00–20:00. (B) The complete regulatory relationship among 24 circadian genes in 18:00–20:00. (C) The target genes regulated by transfer information from 14:00 to 16:00. (D) The rate-limiting gene Aanat is activated by Hif1a, Bach1, Clock, and Per2 in 18:00–20:00. (E) The main mechanism for information transfer process in 18:00–20:00, Hif1a, Bach1, Clock, E2f6, and Per2 are regulated simultaneously by 4 promoter genes, Rel, Polr2A, Mafk, and Srbf1 and contribute genetic information to Aanat. (F) The targeting regulatory relations between promoter genes and Aanat in 18:00–20:00.
Figure 8
Figure 8
The regulatory mechanism of Aanat significant expression process in 20:00–22:00. (A) The time-dependent variation of transfer information among 24 circadian genes in 20:00–22:00. (B) The complete regulatory relationship among 24 circadian genes in 20:00–22:00. (C) The target genes regulated by transfer information from 18:00 to 20:00. (D) The rate-limiting gene Aanat is activated by Hif1a, Bach1, Clock, Per2, Egr1, and Zmiz1 in 20:00–22:00. (E) The main mechanism for information transfer process in 20:00–22:00, Hif1a, Bach1, Clock, E2f6, Per2, Egr1, and Zmiz1 are regulated simultaneously by 4 promoter genes, Rel, Polr2A, Mafk, and Srbf1 and contribute genetic information to Aanat. (F) The targeting regulatory relations between promoter genes and Aanat in 20:00–22:00.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Baba K., Davidson A. J., Tosini G. (2015). Melatonin entrains PER2::LUC bioluminescence circadian rhythm in the mouse cornea. Investig. Ophthalmol. Visual Sci. 56, 4753–4758. 10.1167/iovs.15-17124 - DOI - PMC - PubMed
    1. Bai H. H., Guo X. S., Narisu N., Lan T. M., Wu Q. Z., Xing Y. P., et al. . (2018). Whole-genome sequencing of 175 mongolians uncovers population-specific genetic architecture and gene flow throughout north and east Asia. Nat. Genet. 50, 1696–1704. 10.1038/s41588-018-0250-5 - DOI - PubMed
    1. Binkley S. A. (1983). Circadian rhythms of pineal function in rats. Endocr. Rev. 4, 255–270. 10.1210/edrv-4-3-255 - DOI - PubMed
    1. Cajochen C., Jud C., Munch M., Kobialka S., Wirz-Justice A., Albrecht U. (2006). Evening exposure to blue light stimulates the expression of the clock gene PER2 in humans. Eur. J. Neurosci. 23, 1082–1086. 10.1111/j.1460-9568.2006.04613.x - DOI - PubMed
    1. Castro J. C., Valdes I., Gonzalez-Garcia L. N., Danies G., Canas S., Winck F. V., et al. . (2019). Gene regulatory networks on transfer entropy (GRNTE): a novel approach to reconstruct gene regulatory interactions applied to a case study for the plant pathogen phytophthora infestans. Theor. Biol. Med. Modell. 16, 7. 10.1186/s12976-019-0103-7 - DOI - PMC - PubMed