SkinChronicles, No 3, December 2024, by Marianne Bengtson Løvendorf

Papers:

Yi R, Poy MN, Stoffel M, Fuchs E. A skin microRNA promotes differentiation by repressing ‘stemness’. Nature. 2008 Mar 13;452(7184):225-9. PMID: 18311128.

Sonkoly E, Wei T, Janson PC, Sääf A, et al. MicroRNAs: novel regulators involved in the pathogenesis of psoriasis? PLoS One. 2007 Jul 11;2(7): e610. PMID: 17622355.

On October 7, 2024, the Nobel Prize in Physiology or Medicine was awarded to Victor Ambros and Gary Ruvkun for their groundbreaking discovery of microRNAs (miRNAs). Their research revealed that miRNAs, small non-coding RNAs, play a fundamental role in regulating gene expression across multiple biological systems [1-3]. This discovery has profoundly impacted molecular biology, providing a new lens through which gene expression and regulation can be understood. The pioneering work of Ambros and Ruvkun laid the foundation for numerous studies, including the exploration of miRNA function in human skin.

Two pivotal studies in 2006 showed that microRNAs exist in the mammalian skin and play an important role in its development [4,5]. Building on this foundation, an important study by Yi R. et al. in 2008 identified miR-203 as a skin-specific miRNA with a crucial role in keratinocyte differentiation—the process by which skin cells mature to form the protective outer layer [6]. Using high-throughput sequencing and functional assays, the researchers demonstrated that miR-203 is highly expressed in differentiating keratinocytes and that it acts by repressing the transcription factor p63, which maintains the stemness of keratinocytes. By inhibiting p63, miR-203 drives keratinocytes from a proliferative state to differentiation, which is essential for skin barrier function. These findings significantly advanced our understanding of skin homeostasis and opened new avenues for investigating skin diseases characterized in part by disrupted differentiation processes, such as psoriasis and eczema.

A key study that not only extended the discovery of miRNAs to a human inflammatory skin disease, but also profoundly shaped my personal journey into skin research was conducted by Sonkoly E. et al. [7]. This study captivated my curiosity and became a cornerstone in my exploration of how miRNAs can be used as biomarkers in psoriasis. The researchers used microarray analysis to compare miRNA expression in psoriatic and non-psoriatic skin, identifying among others miR-203 as significantly upregulated in psoriatic lesions. Moreover, their findings reinforced earlier observations that miR-203 is a skin-specific miRNA, highlighting its unique role in keratinocyte biology and its potential as a therapeutic target in skin diseases.

As research into miRNAs in skin biology continues, the future of miRNA research in dermatology holds immense promise, offering exciting opportunities to unravel the complexities of skin biology and transform these insights into innovative therapies for skin health and disease.

References

[1] Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75(5):843-54

[2] Wightman B, Ha I, Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell. 1993;75(5):855-62

[3] Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, Horvitz HR, Ruvkun G. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature. 2000;403(6772):901-6

[4] Yi R, O’Carroll D, Pasolli HA, et al. (2006). Morphogenesis in skin is governed by discrete sets of differentially expressed miRNAs. Nat Genet; 38: 356-62.

[5] Andl T, Murchison EP, Liu F, et al. (2006). The miRNA-processing enzyme dicer is essential for the morphogenesis and maintenance of hair follicles. Curr. Biol; 16: 1041–49.

[6] Yi R, Poy MN, Stoffel M, et al. (2008). A skin microRNA promotes differentiation by repressing “stemness”. Nature; 452: 225-29.

[7] Sonkoly E, Wei T, Janson PC, Sääf A, et al.  MicroRNAs: novel regulators involved in the pathogenesis of psoriasis? PLoS One. 2007 Jul 11;2(7):e610.