Abstract
Intermittent fasting remains a safe and effective strategy to ameliorate various age-related diseases, but its specific mechanisms are not fully understood. Considering that transcription factors (TFs) determine the response to environmental signals, here, we profiled the diurnal expression of 600 samples across four metabolic tissues sampled every 4 over 24 h from mice placed on five different feeding regimens to provide an atlas of TFs in biological space, time, and feeding regimen. Results showed that 1218 TFs exhibited tissue-specific and temporal expression profiles in ad libitum mice, of which 974 displayed significant oscillations at least in one tissue. Intermittent fasting triggered more than 90% (1161 in 1234) of TFs to oscillate somewhere in the body and repartitioned their tissue-specific expression. A single round of fasting generally promoted TF expression, especially in skeletal muscle and adipose tissues, while intermittent fasting mainly suppressed TF expression. Intermittent fasting down-regulated aging pathway and upregulated the pathway responsible for the inhibition of mammalian target of rapamycin (mTOR). Intermittent fasting shifts the diurnal transcriptome atlas of TFs, and mTOR inhibition may orchestrate intermittent fasting-induced health improvements. This atlas offers a reference and resource to understand how TFs and intermittent fasting may contribute to diurnal rhythm oscillation and bring about specific health benefits.
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Data availability
The accession number for the sequences reported in this paper is GEO: GSE154797 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154797). Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Guolin Li (hnsdlgl@hunnu.edu.cn).
Abbreviations
- AL:
-
Ad libitum
- AF:
-
Acute fasting
- AR:
-
Refeeding after acute fasting
- BAT:
-
Brown adipose tissue
- Bmal1 :
-
Brain and muscle ARNT-like 1
- EODF:
-
Every-other-day fasting
- EODR:
-
Every-other-day refeeding
- mTOR:
-
Mammalian target of rapamycin
- PAGE:
-
Parametric analysis of gene set enrichment
- Rorc :
-
RAR-related orphan receptor C
- TFs:
-
Transcription factors
- TSS:
-
Tissue specificity scores
- WAT:
-
White adipose tissue
- ZT:
-
Zeitgeber time
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Acknowledgements
We thank Lin Zheng, Qiu Wang, Qian Zhang, Lijun Chen, Baode Zhu, Guangyao Wu, Lu Wang, Lijiao Zhu, Han Liu, Siyu Wang, Xiaoli Zeng, Yu Liang, Yuebo Wang, Xiaomin Xia, Juan Wang, and Tingting Zhang for assistance with the daily feeding of mice and tissue collection; Yong Zeng and Yujie Yan for assistance with bioinformatics assay; and LC Science Facility for help with sequencing.
Funding
G.L. was supported by the National Natural Science Foundation of China (31871198) and the Opening Fund of The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development (Hunan Normal University, National Development and Reform Commission). F.W. was supported by the National Natural Science Foundation of China (81903138) and the Natural Science Foundation of Hunan Province (2022JJ30413). F.J.G was supported by the National Cancer Institute Intramural Research Program. The funding sponsors had no role in the writing of the manuscript and in the decision to submit the manuscript for publication.
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Contributions
GL designed and conceived the experiments. GL, MF, LG, SL, YZ, and FW conducted experiments. GL and FW performed the bioinformatics analysis. MF participated in project management. GL, ZD, and RX contributed to interpretation of results. GL, FW and FJG wrote the manuscript.
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The authors declare no competing interests.
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All mouse studies were approved by the Institutional Review Board of the Hunan Normal University and performed according to the Laboratory Animal Resources guidelines.
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Supplementary Information
Below is the link to the electronic supplementary material.
11010_2024_4928_MOESM1_ESM.pdf
Supplementary Fig. 1. The statistics of transcription factors across different tissues in AL mice, Related to Fig. 2. A) The Venn diagram displaying the overlap numbers of TFs expressed in different tissues of AL mice. B) The Venn diagram showing the overlap numbers of TFs with tissue specificity scores more than 5 in different tissues of AL mice. C) The Venn diagram demonstrating the overlap numbers of oscillated TFs in different tissues of AL mice. D) The number of oscillated TFs in AL mice illustrating the oscillatory phases in different tissues. TFs, transcription factors; AL, ad libitum; BAT, brown adipose tissue; WAT, white adipose tissue; ZT, zeitgeber time
Supplementary file1 (PDF 255 KB)
11010_2024_4928_MOESM2_ESM.pdf
Supplementary Fig. 2. The statistics of differentially expressed transcription factors under different feeding regimens, Related to Fig. 3. A-B) The statistics of tissue-specific TFs upregulated (A) or down-regulated (B) by different feeding modifications. TFs, transcription factors; AL, ad libitum; AF, acute fasting; AR, refeeding after acute fasting; EODF, every-other-day fasting; EODR, every-other-day refeeding; BAT, brown adipose tissue; WAT, white adipose tissue
Supplementary file2 (PDF 307 KB)
11010_2024_4928_MOESM3_ESM.pdf
Supplementary Fig. 3. The oscillatory profile of transcription factors in four metabolic tissues of mice under different feeding regimens, Related to Fig. 4. Heat maps showing oscillatory TFs in the liver, skeletal muscle, BAT and WAT of mice under different feeding regimens (n = 5). Six columns in each heat map from left to right are ZT16, ZT20, ZT0, ZT4, ZT8 and ZT12, respectively. Cells are shaded according to Z scores from − 2 to 2 (green for low, blue for high). The heat maps of AL mice were the copy of Fig. 2B, in order to show the different between AL and other treatments. TFs, transcription factors; AL, ad libitum; AF, acute fasting; AR, refeeding after acute fasting; EODF, every-other-day fasting; EODR, every-other-day refeeding; BAT, brown adipose tissue; WAT, white adipose tissue; ZT, zeitgeber time
Supplementary file3 (PDF 1728 KB)
11010_2024_4928_MOESM4_ESM.pdf
Supplementary Fig. 4. The Venn diagram demonstrating the overlap numbers of oscillated TFs in different tissues of AL mice, Related to Fig. 4
11010_2024_4928_MOESM5_ESM.pdf
Supplementary Fig. 5. The statistics of oscillatory transcription factors before and after normalized to AL rhythm, Related to Fig. 4. The statistics of oscillatory TFs before (Original) and after (FC to AL) normalized to AL rhythm illustrating the change induced by the normalization. TFs, transcription factors; AL, ad libitum; AF, acute fasting; AR, refeeding after acute fasting; EODF, every-other-day fasting; EODR, every-other-day refeeding; FC, fold changeSupplementary file4 (PDF 175 KB)
Supplementary file5 (PDF 1161 KB)
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Supplementary Fig. 6. The oscillatory signatures of transcription factors induced by different feeding modifications, Related to Fig. 4. A) The number of oscillatory TFs before and after normalized to the rhythm of AL mice in different tissues under different feeding regimens (n = 5). B-E) The Venn diagrams displaying the overlap numbers of rhythmic TFs across different tissues induced by AF (B), AR (C), EODF (D) and EODR (E) after normalized against the diurnal rhythm of AL mice (n = 5). F) Heat maps showing the tissue-specific oscillatory signatures of TFs induced by different feeding modifications after normalized against the rhythm of AL mice (n = 5). Six columns in each heat map from left to right are ZT16, ZT20, ZT0, ZT4, ZT8 and ZT12, respectively. Cells are shaded according to Z scores from − 2 to 2 (green for low, blue for high). AL, ad libitum; AF, acute fasting; AR, refeeding after acute fasting; EODF, every-other-day fasting; EODR, every-other-day refeeding; BAT, brown adipose tissue; WAT, white adipose tissue; ZT, zeitgeber time; FC, fold change
Supplementary file6 (PDF 339 KB)
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Supplementary Fig. 7. The rhythmic expression of canonical clock transcription factors induced by different feeding modifications, Related to Fig. 2. A–D) The rhythmic signatures of canonical diurnal clock TFs in different tissues induced by AF (A), AR (B), EODF (C) and EODR (D) after normalized against the diurnal rhythm of AL mice (n = 5). Shadow represents night. AL, ad libitum; AF, acute fasting; AR, refeeding after acute fasting; EODF, every-other-day fasting; EODR, every-other-day refeeding; BAT, brown adipose tissue; WAT, white adipose tissue; ZT, zeitgeber time. Data are represented as mean ± SEM.
Supplementary file7 (PDF 880 KB)
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Supplementary Fig. 8. Intermittent fasting shifts diurnal expressive patterns of aging and autophagy pathways, Related to Fig. 5. Z scores were calculated by parametric analysis of gene set enrichment (PAGE), and normalized to AL mice sacrificed at ZT16. AL, ad libitum; AF, acute fasting; AR, refeeding after acute fasting; EODF, every-other-day fasting; EODR, every-other-day refeeding; BAT, brown adipose tissue; WAT, white adipose tissue; ZT, zeitgeber time
Supplementary file8 (PDF 752 KB)
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Supplementary Table 1. The mean of FPKM values in mice fed ad libitum, Related to Fig. 2
Supplementary file9 (XLSX 1726 KB)
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Supplementary Table 2 Tissue specificity scores of transcription factors in mice fed ad libitum, Related to Fig. 2
Supplementary file10 (XLSX 503 KB)
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Supplementary Table 3. Oscillation profiles of transcription factors in mice under different feeding regimens, Related to Fig. 2
Supplementary file11 (XLSX 408 KB)
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Supplementary Table 4 Tissue-specific expressive pattern of transcription factors in mice under different feeding regimens, Related to Fig. 3
Supplementary file12 (XLSX 431 KB)
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Supplementary Table 5 Feeding modifications induced oscillation profiles of transcription factors after normalized to the rhythm of mice fed ad libitum, Related to Fig. 4
Supplementary file13 (XLSX 320 KB)
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Fu, M., Lu, S., Gong, L. et al. Intermittent fasting shifts the diurnal transcriptome atlas of transcription factors. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-04928-y
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DOI: https://doi.org/10.1007/s11010-024-04928-y