An expression screen for aged-dependent microRNAs identifies miR-30a as a key regulator of aging features in human epidermis

Abstract

The mechanisms affecting epidermal homeostasis during aging remain poorly understood. To identify age-related microRNAs, a class of non-coding RNAs known to play a key role in the regulation of epidermal homeostasis, an exhaustive miRNA expression screen was performed in human keratinocytes from young or elderly subjects. Many microRNAs modulated by aging were identified, including miR-30a, in which both strands were overexpressed in aged cells and epidermal tissue. Stable MiR-30a over-expression strongly impaired epidermal differentiation, inducing severe barrier function defects in an organotypic culture model. A significant increase was also observed in the level of apoptotic cells in epidermis over-expressing miR-30a. Several gene targets of miR-30a were identified in keratinocytes, including LOX (encoding lysyl oxidase, a regulator of the proliferation/differentiation balance of keratinocytes), IDH1 (encoding isocitrate dehydrogenase, an enzyme of cellular metabolism) and AVEN (encoding a caspase inhibitor). Direct regulation of LOX, IDH1 and AVEN by miR-30a was confirmed in human keratinocytes. They were, moreover, observed to be repressed in aged skin, suggesting a possible link between miR-30a induction and skin-aging phenotype. This study revealed a new miRNA actor and deciphered new molecular mechanisms to explain certain alterations observed in epidermis during aging and especially those concerning keratinocyte differentiation and apoptosis.

Peer Review #3 of "Identification of microRNA signatures in umbilical cord blood associated with maternal characteristics (v0.1)"

“…For example, miR-625-3p and miR-671-3p showing significant association with maternal age in our study were described also in study of Huan et al as age-associated miRNAs [23]. Moreover, miR-671-3p seems to be differentially expressed between keratinocytes prepared from child skin and aged skin [24]. Similarly, we identified miRNAs indicating association with maternal BMI or weight gain during pregnancy.…”

The Role of MicroRNAs in Epidermal Barrier

“…Upregulation of JNK by galectin-7 [19] Increased keratinocyte differentiation with involucrin expression by oleic acid [20] p63, Skp2 and Msi2 Promotion of cell cycle exit in mouse skin [21] miR-574 ↑ p63 As direct targets of iASPP [22] miR-720 ↑ miR-24 ↑ PAK4 Control of actin cable formation [23] miR-23b-3p ↑ TGIF1 Interference in TGF-β/SMAD signaling [24] miR-378b ↑ NKX3.1 [25] miR-30a ↑ LOX, IDH1, AVEN Barrier function defects in aged epidermis [26] miR-184 ↑ Upregulation of cyclin E and p21 cyclin-dependent kinase inhibitor in a SOCE-dependent manner [27] miR-181a ↑ cell differentiation under high calcium or UVA exposure [28,29] miR [33] miRNAs targeted by p63 miR-34a ↑ SIRT6 miR-34a and miR-34c as direct targets of p63 [34,35] miR-34a ↑ KLK4 Induction of a senescent phenotype in keratinocytes [36] ↑: upregulation (increase), ↓: downregulation (decrease).…”

“…Defective barrier function is related to aged epidermis. Investigation of the role of miRNAs in age-related keratinocyte differentiation and barrier function revealed that the upregulation of miR-30a in human keratinocytes treated with calcium [28] results in impaired keratinocyte differentiation and barrier defects mediated via lysyl oxidase (LOX), isocitrate dehydrogenase 1 (IDH1), and apoptosis and caspase activation inhibitor (AVEN) [26].…”

New Insights for Cellular and Molecular Mechanisms of Aging and Aging-Related Diseases: Herbal Medicine as Potential Therapeutic Approach

“…Some researchers constructed a Drosophila model of skin aging and found that the increased expression of the autophagy marker, Atg7, was associated with skin aging [162]. Another study found that exosome miR-30a can regulate the apoptosis of epidermal cells, and its overexpression led to impaired epidermal differentiation by directly targeting AVEN (encodes a caspase inhibitor), IDH1 (encodes isocitrate dehydrogenase, an enzyme of cellular metabolism), and LOX (encodes lysyl oxidase, a regulator of the proliferation/differentiation balance of keratinocytes), inducing severe barrier dysfunction and skin aging [163]. Treatment for skin aging mainly includes oral antioxidant drugs, topical antiaging agents, and photoelectric and acoustic physical technology.…”