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Sexual dimorphism of monocyte transcriptome in individuals with chronic low-grade inflammation.

ABSTRACT: Sexual dimorphism in the immune system is evidenced by a higher prevalence of autoimmune diseases in women and higher susceptibility to infectious diseases in men. However, the molecular basis of these sex-based differences is not fully understood. We have characterized the transcriptome profiles of peripheral blood monocytes from males and postmenopausal females with chronic low-grade inflammation. We identified 41 sexually differentially expressed genes [adjusted p value (FDR) < 0.1], including genes involved in immune cell activation (e.g., CEACAM1, FCGR2B, and SLAMF7) and antigen presentation (e.g., AIM2, CD1E, and UBA1) with a higher expression in females than males. Moreover, signaling pathways of immune or inflammatory responses, including interferon (IFN) signaling [z-score = 2.45, -log(p) = 3.88], were found to be more upregulated in female versus male monocytes, based on a set of genes exhibiting sex-biased expression (p < 0.03). The contribution of IFN signaling to the sexual transcriptional differences was further confirmed by direct comparisons of the monocyte sex-biased genes with IFN signature genes (ISGs) that were previously curated in mouse macrophages. ISGs showed a greater overlap with female-biased genes than male-biased genes and a higher overall expression in female than male monocytes, particularly for the genes of antiviral and inflammatory responses to IFN. Given the role of IFN in immune defense and autoimmunity, our results suggest that sexual dimorphism in immune functions may be associated with more priming of innate immune pathways in female than male monocytes. These findings highlight the role of sex on the human immune transcriptome.

SUBMITTER: So J

PROVIDER: S-EPMC8320037 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Purpose: To conduct a transcriptomic study of gene oscillations in mouse liver by RNA sequencing of total RNA samples from 6 different time points across the day. Specific interest is to see whether sex is a factor in large scale gene oscillations under ad-libitum control conditions and in response to caloric restriction diet, since caloric restriction was previously reported to affect gene oscillation Methods: Total RNA was isolated from 20 mg mouse liver tissue using mini spin column QIAGEN RNeasy Mini Kit (Ref #74104, Lot#163035346, Hilden, Germany) according to the manufacturer’s protocol. Sample purity was checked on Nano Drop 2000 (Thermo Fisher Scientific, Waltham, MA, USA) with 260/280 ratio ≥ 2.0 and 260/230 ratio ≥ 2.0 for every sample. Each sample used for the analysis had RNA integrity number > 7. The RNA sequencing was performed by Novogene Corporation Inc (Sacramento, CA, USA). After sample quality control, non-directional – polyA enrichment library was prepared using NEBNext Ultra™ II RNA Library Prep Kit for Illumina, and 50M reads (150bp, paired end) per sample were generated on Illumina NovaSeq 6000 platform. RNA-seq reads were mapped to the mouse protein coding genes (Ensembl: Mus_musculus; GRCm38) using Bowtie allowing up to 2-mismatches. The gene expected read counts and Transcripts Per Million (TPM) were estimated by RSEM (v1.2.3). The TPMs were further normalized by EBSeq R package to correct potential batch effect. Results: We have performed RNA sequencing analysis of mouse livers on Ad-libitum and timed Caloric Restriction diet across 6 time points in 24h. The results of subsequent JTK_Cycle analysis (R package) revealed that circadian rhythms in total RNA liver transcriptome are different between sexes of mice in both the number of oscillating genes and phase under ad-libitum diet. Caloric restriction increased the number of oscillating genes in both sexes and resulted in a larger overlap of rhythmic transcriptome between sexes, but did not eliminate the difference completely. The response of transcriptome to caloric restriction in terms of gain or loss of rhythm in gene expression profiles was also different between sexes. Additionally, we have shown that the lack of data stratification by sex might result in the failure to detect rhythmic changes in expression of some genes. Conclusions: Our study represents the first systematic analysis of the effect of sex on circadian rhythms of liver transcriptome under ad libitum and caloric restriction diets. We have shown that sex based differences exist in rhythmic transcriptome, as well as in the response of rhythmic transcriptome to diet. We are providing the data useful for both circadian and metabolic researchers and point out the gene candidates which may not be identified as rhythmic, if the data is not stratified by sex. With the help of GO analysis we have concluded that sex also influences the preference towards different processes to be regulated in rhythmic manner on transcriptional level - fatty acid metabolism and protein transport in males vs nucleic acid metabolism and RNA processing in females on ad-libitum diet. On calorie-restricted diet nucleic acid metabolism and RNA processing were enriched in males vs protein transport and signal transduction in females on calorie-restricted diet. These findings highlight a complex interaction of sex and diet in their effect on circadian rhythms in liver gene expression. All of the data from sequenced RNA samples from MALE liver were previously uploaded with the GSE211975 dataset. The current dataset only contains RNA-seq samples from FEMALE liver.

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Sexual dimorphism of monocyte transcriptome in individuals with chronic low-grade inflammation.

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