The human‐specific noncoding RNA RP11‐424G14.1 functions at the intersection of sexually dimorphic pathways in inflammation, senescence, and metabolism
Abstract Sexual dimorphism is a fundamental characteristic of various physiological and pathological processes in humans, including immune responses, senescence, and metabolism. Most studies on the sex bias have focused on sex hormones or female‐biased genes, whereas male‐biased genetic factors rema...
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| Main Authors: | , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-02-01
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| Series: | FASEB BioAdvances |
| Subjects: | |
| Online Access: | https://doi.org/10.1096/fba.2024-00101 |
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| Summary: | Abstract Sexual dimorphism is a fundamental characteristic of various physiological and pathological processes in humans, including immune responses, senescence, and metabolism. Most studies on the sex bias have focused on sex hormones or female‐biased genes, whereas male‐biased genetic factors remain understudied. Here, we show that the Y‐linked noncoding RNA, RP11‐424G14.1, is expressed in human male keratinocytes. Microarray study suggests the NF‐κB pathway as the top biological pathway affected by RP11‐424G14.1 knockdown, consistent with known sex differences in inflammation. Additionally, IGFBP3 is identified as the top gene supported by RP11‐424G14.1 in male keratinocytes. Conversely, in female keratinocytes, IGFBP3 is the top gene repressed by the X‐linked long noncoding RNA XIST, suggesting a central role of IGFBP3 in mediating sexual dimorphism. Knockdown of RP11‐424G14.1 or IGFBP3 in male keratinocytes inhibits cellular senescence, consistent with increased longevity in females. IGFBP3 expression is dependent on insulin, and metabolomics analysis suggests that RP11‐424G14.1 and IGFBP3 regulate acrylcarnitine metabolism. Our study identifies the role of the RP11‐424G14.1‐IGFBP3 pathway in coordinating sex differences in immunity, senescence, and metabolism. With RP11‐424G14.1 being a human‐specific genetic element, our study suggests the evolving feature of sexual dimorphisms in biological processes. |
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| ISSN: | 2573-9832 |