Friends who want to study the feedforward loop quickly look over

I believe that many people still remember Mark Kelly and Scott Kelly’s twin astronaut experiments.
In order to study the effects of outer space on the human body, Scott was asked to be on the International Space Station between 2015 and 2016.
Lived for 340 days, while his twin brother Mark stayed on Earth as a control group.

Studies have found that the microgravity environment of space (ie, weightlessness environment) will cause astronauts to undergo a series of physiological and pathological changes, including immune stress, vascular changes and bone loss (when in a weightless environment, the pressure on the body’s weight-bearing bones) Abruptly).

The article I want to share with you today is similar to NASA’s twin experiment.
It studies the impact of microgravity on the human system and tumorigenesis from the perspective of TF-miRNA feed-forward loops (FFLs), published in International Journal of Molecular Sciences (IF: 4.
556).

Research background: Understanding how microgravity affects human health is crucial for astronauts.

TF and miRNA are the main factors that regulate gene expression at the transcription level and post-transcription level, and can coordinately regulate the same target gene by forming TF-miRNA FFL.

For TF-miRNA FFL under microgravity, there is no systematic study yet.

The relationship between microgravity and various cancers remains unclear.

Research data: The gene and miRNA expression profiles were downloaded from GEO database (GSE57408 and GSE57400).
The data was obtained by Girardi et al.
in the microgravity and normal gravity environment of the peripheral blood lymphocytes of five healthy donors; from TCGA Download cancer gene expression data (level 3) from the database; get the regulation of genes by TF from the TRANSFAC Professional database; get the regulation of genes by miRNA from the TarBase v8, miRTarbase and TRANSFAC Professional databases; get the regulation of genes by miRNA from TransmiR v2.
0 and TRANSFAC Professional The regulation of miRNA by TF is obtained from the database.

Research method: Identification of disordered FFL: (1) Score the degree of differential expression of each node in the TF-miRNA regulatory network; (2) Score the degree of differential co-expression of each edge in the TF-miRNA regulatory network ——According to the difference of gene co-expression between microgravity and normal samples; (3) FFL score is equal to the weighted sum of node score and edge score, and permutation test is used to evaluate the significance of each FFL score, with p value less than or equal to 0.
05 FFL is considered a dysregulated FFL.

Research results: 1.
The characteristics of the TF-miRNA regulatory network The regulatory network contains 647 TF, 888 miRNA and 3794 genes.

By analyzing the topological properties of the network, it is found that it is similar to most biological networks.
The degree distribution of the background control network shows a power-law distribution, which satisfies the scale-free nature.

2.
FFL disorders under microgravity 1) 4064 FFLs and 230 dysregulated FFLs were identified in the TF-miRNA regulatory network.

FFL includes the following three types (see Figure 1): a.
TF-FFL: TF regulates miRNA and genes at the transcriptional level, and miRNA inhibits gene expression at the post-transcriptional level; b.
miRNA-FFL: miRNA inhibits TF and genes, and TF regulates Gene; c, FB-FFL: TF and miRNA regulate each other, and both regulate the same target gene. Figure 1.
Three FFL types 2) Through functional enrichment analysis of genes and miRNAs in dysregulated FFL, it is found that they are mainly enriched in immune system-related pathways and cancer-related pathways (Figure 2D, E).

3) Define the FFL of the TF-miRNA regulatory network with a degree greater than or equal to 10 as hub FFL, and a total of 31 hub FFLs are obtained; the hub FFL subnet is constructed by connecting hub FFLs (as shown in Figure 2F), which includes 10 TFs, 8 1 miRNA and 5 genes.

4) Eight (~53%) genes in the hub FFL subnet are known CGC cancer genes, and their proportion is significantly higher than that of the dysregulated FFL network and the background regulatory network (Figure 2G).

Figure 2.
Functional analysis of dysregulated FFL 3.
The influence of microgravity on the multibody system 1) KEGG function annotation analysis was performed on genes and miRNAs in dysregulated FFL through DAVID and DIANA-miRPath; if all nodes in FFL are involved in the human body System (including immune system, cardiovascular system, skeletal system, endocrine system, nervous system) related pathways, then it is defined as "system function related FFL".

Figure 3.
System function related FFL 2) By merging each system function related FFL, five subnets are constructed: Figure 4.
Five human system subnets 3) The author shows the overlap of nodes in the five subnets (Figure 5A, B); and found that there are three modules shared by three (or more) subnets (as shown in Figure 5C), that is, imbalanced FFL will have a systemic impact on the human body, and different body systems may cooperate with each other.

Figure 5.
Subnet analysis of five human systems.
IV.
The effect of microgravity on bone loss and drug screening 1) The author analyzed the gene and miRNA expression in the skeletal system subnet (Figure 6D).

2) Disorders of genes and miRNAs may lead to bone loss, which is one of the most common diseases of astronauts during space flight.

In order to reduce the impact of microgravity on bone loss, the authors used the SM2miR database to screen drugs that can alter the expression of miRNA and genes in the subnet, and found that two traditional Chinese medicines, emodin and ginsenoside Rh2, can inhibit hsa-miR-221-3p and hsa -The expression of miR-125b-5p (Figure 6E).

Figure 6.
Screening candidate drugs related to bone loss 5.
In-depth understanding of the relationship between microgravity and cancer 1) The Wilcoxon rank sum test was used to analyze the expression values ​​of significantly differentially expressed genes in 20 cancer types and those under microgravity The relative change of log2FC distribution (Figure 7A); 2) DAVID was used to analyze the significantly disturbed pathways co-existing in the microgravity environment and cancer (Figure 7B).

3) The author also found that there are six genes that are down-regulated in microgravity and rectal cancer (Figure 7C), and are enriched in the "intestinal immune network to produce IgA" pathway (Figure 7D).

Figure 7.
The relationship between microgravity and cancer.
Summary of the article: In this study, the author systematically analyzed the effects of microgravity on five human systems and the relationship between microgravity and cancer.

The author found 230 dysfunctional FFLs in a microgravity environment, and constructed subnets of the human system based on the functions of FFLs, including immune, cardiovascular, skeletal, endocrine and nervous system subnets.

The authors also predict that the candidate drugs emodin and ginsenoside Rh2 can reverse the dysregulated expression of miRNAs, thereby preventing or reducing bone loss due to microgravity.

Finally, the author studied the relationship between microgravity and cancer and found that microgravity may promote most cancers.

For example, microgravity inhibits immune protection by reducing antigen presentation and inhibiting the migration of cells secreting IgA antibodies, thereby promoting the formation of rectal adenocarcinoma.

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