Network Analysis Identifies Mitochondrial Regulation of Epidermal Differentiation by MPZL3 and FDXR
Open accessAbstract
Current gene expression network approaches commonly focus on transcription factors (TFs), biasing network-based discovery efforts away from potentially important non-TF proteins. We developed proximity analysis, a network reconstruction method that uses topological constraints of scale-free, small-world biological networks to reconstruct relationships in eukaryotic systems, independent of subcellular localization. Proximity analysis identified MPZL3 as a highly connected hub that is strongly induced during epidermal differentiation. MPZL3 was essential for normal differentiation, acting downstream of p63, ZNF750, KLF4, and RCOR1, each of which bound near the MPZL3 gene and controlled its expression. MPZL3 protein localized to mitochondria, where it interacted with FDXR, which was itself also found to be essential for differentiation. Together, MPZL3 and FDXR increased reactive oxygen species (ROS) to drive epidermal differentiation. ROS-induced differentiation is dependent upon promotion of FDXR enzymatic activity by MPZL3. ROS induction by the MPZL3 and FDXR mitochondrial proteins is therefore essential for epidermal differentiation.
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A frame-shift mutation in ZNF750, a transcription factor controlling epidermal differentiation and an upstream regulator of MPZL3, caused autosomal dominant seborrhea-like dermatitis in patients.
“Interestingly, a frame-shift mutation in ZNF750, a transcription factor controlling epidermal differentiation and an upstream regulator of MPZL3, caused autosomal dominant seborrhea-like dermatitis in patients [71,86].”
From Seborrheic Dermatitis and Dandruff: A Comprehensive Review (2015) · cites this paper as [86]
The Results section ('MPZL3 is required for normal epidermal differentiation'; page unavailable) identifies ZNF750 as a regulator of epidermal differentiation and shows that it regulates MPZL3. Our copy does not report a ZNF750 frameshift mutation or autosomal dominant seborrhea-like dermatitis in patients, so it supports only the regulatory part of the sentence. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSkin abnormalities in Mpzl3 knockout mice and perturbed epidermal differentiation in organotypic human skin models with MPZL3 knockdown indicate that MPZL3 is a key regulator of epidermal differentiation.
“However, skin abnormalities in Mpzl3 knockout mice and perturbed epidermal differentiation in organotypic human skin models with MPZL3 knockdown indicate that MPZL3 is a key regulator of epidermal differentiation [85,86].”
From Seborrheic Dermatitis and Dandruff: A Comprehensive Review (2015) · cites this paper as [86]
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- Authors
- Bhaduri, A., Ungewickell, A., Boxer, L. D., Lopez-Pajares, V., Zarnegar, B. J., & Khavari, P. A.
- Affiliations
- Stanford Medicine (US)
- VA Palo Alto Health Care System (US)
- Corresponding author
- Khavari, Paul A.
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 35
- Issue
- 4
- Pages
- 444-457
- ISSN
- 1534-5807 (ISSN-L)
- PMC
- PMC4845910
- OpenAlex
- W2179199957
- Cited by
- 60
- References
- 57
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 2 · 2023: 4 · 2022: 9 · 2021: 5 · 2020: 4 · 2019: 6 · 2018: 11 · 2017: 7 · 2016: 2 · 2015: 2
- FWCI
- 3.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (NCI F310CA180408, F31CA180408, T32CA009302)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS NIH R01 AR45192, R01AR045192)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Health Sciences › Medicine › Urology › Hair Growth and Disorders
- Keywords
- ferredoxin reductase, epidermal differentiation, proximity analysis, gene regulatory networks, mitochondrial proteins, reactive oxygen species, p63, ZNF750, KLF4, transcriptional regulation, hub genes, scale-free networks
- MeSH terms
- Epidermal Cells, Kruppel-Like Factor 4, Cell Differentiation, Cells, Cultured, Epidermis, Ferredoxin-NADP Reductase, Ferredoxins, Gene Expression Regulation, Humans, Membrane Proteins, Mitochondria, Transcription Factors, Keratinocytes, Reactive Oxygen Species, Mitochondrial Proteins, RNA, Small Interfering, Gene Regulatory Networks, Metabolomics
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