Epidermal loss of PRMT5 leads to the emergence of an atypical basal keratinocyte-like cell population and defective skin stratification

Nicole Recka; Andrean Simons; Robert A Cornell; Eric Van Otterloo

doi:10.1016/j.jid.2025.04.008

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Epidermal loss of PRMT5 leads to the emergence of an atypical basal keratinocyte-like cell population and defective skin stratification

Journal article

Peer reviewed

Epidermal loss of PRMT5 leads to the emergence of an atypical basal keratinocyte-like cell population and defective skin stratification

Nicole Recka, Andrean Simons, Robert A Cornell and Eric Van Otterloo

Journal of investigative dermatology, pp.3100-3114.e14

12/2025

DOI: 10.1016/j.jid.2025.04.008

PMCID: PMC12239857

PMID: 40339790

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https://pmc.ncbi.nlm.nih.gov/articles/PMC12239857/View

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Abstract

During skin development, ectoderm-derived cells undergo precisely coordinated proliferation, differentiation, and adhesion to yield stratified epidermis. Disruptions in these processes can result in congenital anomalies including ectodermal dysplasia and harlequin ichthyosis. Protein Arginine Methyl Transferase 5 (PRMT5)-an enzyme responsible for methylating arginine residues in histones and other proteins-maintains progenitor status in germ and limb bud cells. Similarly, in vitro evidence suggests that PRMT5 prevents differentiation of basal keratinocytes, leading us to hypothesize that PRMT5 preserves the stem-cell phenotype of keratinocytes in vivo. To test this possibility, we generated conditional knockout (cKO) mice lacking Prmt5 in early ectoderm (E7.5), impacting the entire epidermis. Prmt5 cKOs exhibited gross skin defects, compromised skin barrier function, and reduced postnatal viability. Histological analyses revealed significant defects in epidermal stratification, without alterations in apoptosis or proliferation. Single-cell RNA and ATAC-seq analysis identified an atypical population of basal keratinocyte-like cells in Prmt5 cKOs, that exhibited a senescence-like program, characterized by increased Cdkn1a (p21), elevated senescence-associated secretory phenotype (SASP) molecules (Igfbp2), and decreased developmental transcription factor (Trp63) expression. Our findings suggest that PRMT5 prevents basal keratinocyte senescence by repressing Cdkn1a, shedding light on the epigenetic regulation of basal keratinocyte maintenance and senescence in congenital skin disorders.

Cell Biology

Developmental Biology

Epigenetics

Mouse Genetics

Keratinocyte Differentiation

Details

Title: Subtitle: Epidermal loss of PRMT5 leads to the emergence of an atypical basal keratinocyte-like cell population and defective skin stratification
Creators: Nicole Recka - University of Iowa
Andrean Simons - University of Iowa
Robert A Cornell - University of Washington
Eric Van Otterloo - University of Iowa
Resource Type: Journal article
Publication Details: Journal of investigative dermatology, pp.3100-3114.e14
DOI: 10.1016/j.jid.2025.04.008
PMID: 40339790
PMCID: PMC12239857
NLM abbreviation: J Invest Dermatol
ISSN: 1523-1747
eISSN: 1523-1747
Publisher: Elsevier
Language: English
Electronic publication date: 05/06/2025
Date published: 12/2025
Academic Unit: Oral Pathology, Radiology and Medicine; Anatomy and Cell Biology; Pathology; Pharmaceutical Sciences and Experimental Therapeutics; Radiation Oncology; Craniofacial Anomalies Research Center; Dental Research; Periodontics
Record Identifier: 9984820561502771

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