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Published on: March 1, 2022
A novel ZIC1-BMP4 axis identified in photoaged dermal fibroblasts regulates melanogenesis
Mengting Ouyang1, Feng Zhou1, Lei Wen1
1Department of Dermatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Background:
Chronic ultraviolet exposure induces photoaging and pigmentation, contributing to disorders such as melasma. However, treatments for photoaging-related pigmentation still challenging, implying upstream regulators remain incompletely understood.
Objectives:
To identify the key regulators involved in photoaging-related pigmentation.
Methods:
We integrated bulk RNA-seq data of sun-exposed and sun-protected human skin from GTEx dataset and validated with public single-cell RNA-seq data. More than 19,000 genes were screened for correlation with MITF, the key regulator of melanogenesis. Cell states and interactions were further characterized using pySCENIC, pseudotime trajectory analysis, and CellChat. Experimental analyses, including immunohistochemistry, immunofluorescence, ChIP-PCR, and ex vivo human skin culture, were performed to further characterize the biological relevance of the transcriptomic findings.
Results:
ZIC1 was identified as a fibroblast-specific transcription factor upregulated in photoaged skin and strongly correlated with MITF. It was enriched in fibroblast subsets associated with inflammation and extracellular matrix remodeling, which displayed enhanced BMP4 signaling to melanocytes. Immunostaining confirmed ZIC1 upregulation in sun-exposed and melasma skin, with colocalization in vimentin-positive fibroblasts. Repeated UVA exposure upregulated both ZIC1 and BMP4 in dermal fibroblasts. Gain- and loss-of-function studies, combined with in silico analysis and ChIP-PCR assay, support a positive regulatory link between ZIC1 and BMP4 during photoaging.
Conclusions:
Our transcriptomic analyses together with preliminary experimental verification suggest a previously unrecognized ZIC-BMP4 axis through which dermal fibroblasts implicated in melanogenesis in photoaged skin, providing new insights into dermal-epidermal crosstalk and highlighting a potential therapeutic target.
Insights
Researchers identified ZIC1 as a key regulator in photoaging-related skin pigmentation. This fibroblast-specific factor influences melanogenesis through the ZIC1-BMP4 axis, offering a potential therapeutic target for melasma and other pigmentation disorders.
Area of Science:
- Dermatology and Molecular Biology
- Skin Aging and Pigmentation Research
- Transcriptomics and Bioinformatics
Background:
- Chronic ultraviolet (UV) radiation exposure causes skin photoaging and pigmentation disorders like melasma.
- Current treatments for photoaging-induced pigmentation are challenging, indicating a need to understand upstream regulatory mechanisms.
Purpose of the Study:
- To identify key gene regulators involved in skin pigmentation associated with photoaging.
- To elucidate the molecular pathways linking dermal fibroblasts and melanocytes in UV-induced pigmentation.
Main Methods:
- Integrated bulk and single-cell RNA sequencing data from sun-exposed and protected human skin.
- Screened over 19,000 genes for correlation with microphthalmia-associated transcription factor (MITF).
- Utilized pySCENIC, pseudotime analysis, CellChat, immunohistochemistry, and ex vivo skin cultures for validation.
Main Results:
- Identified ZIC1, a fibroblast-specific transcription factor, as upregulated in photoaged skin and correlated with MITF.
- ZIC1 upregulation in fibroblasts was linked to enhanced BMP4 signaling towards melanocytes.
- Confirmed ZIC1 and BMP4 upregulation in response to UVA exposure and demonstrated a regulatory link between them.
Conclusions:
- A novel ZIC1-BMP4 signaling axis in dermal fibroblasts contributes to melanogenesis in photoaged skin.
- This axis provides new insights into dermal-epidermal crosstalk in skin pigmentation.
- The ZIC1-BMP4 pathway represents a potential therapeutic target for photoaging-related pigmentation disorders.
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