The Citrullinating Enzyme PADI4 Governs Progenitor Cell Proliferation and Translation in Developing Hair Follicles

September 2025 in “ Science Advances ”

Kim Vikhe Patil, Nil Campamà Sanz, Kylie Hin-Man Mak, Wei Yang, Karl Annusver, Jasson Makkar, David Grommisch, Li Lei, Priyanka Sharma, Ryan R. Driskell, Maria Kasper, Maria Genander

PADI4 citrullination progenitor cell proliferation hair follicle development peptidylarginine citrulline mRNA processing ribosomal biogenesis protein synthesis ribosomal RNA transcription 4E-BP1 translational repressor posttranslational modifications

Studysummary This study reports that PADI4, an enzyme involved in posttranslational protein modifications, regulates progenitor cell transitions in hair follicle development by repressing transcription and interacting with translational and ribosomal processes.

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This study explores the role of the enzyme PADI4 in hair follicle development, particularly its effect on progenitor cell proliferation and protein translation. PADI4 acts as a negative regulator, restricting proliferation in LEF1-positive progenitor cells, which results in longer hair shafts in PADI4 knockout mice. The enzyme citrullinates proteins involved in mRNA processing and ribosomal biogenesis, leading to increased protein synthesis and ribosomal RNA transcription when absent. PADI4 also interacts with the translational inhibitor 4E-BP1, affecting its function. The research, involving 15 mouse skin samples, highlights PADI4's significant role in balancing proliferation and differentiation in hair follicle progenitor cells, offering insights into hair growth and potential therapeutic strategies for hair loss.

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5 citations , December 2021 in “Frontiers in Cell and Developmental Biology”

This review outlines how peptidyl arginine deiminases (PADIs) and protein citrullination are involved in hair follicle regeneration and inflammatory alopecia, but presents no new clinical findings.

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research Temporal Layering of Signaling Effectors Drives Chromatin Remodeling During Hair Follicle Stem Cell Lineage Progression

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This study found that synchronized signals in the microenvironment regulate stem cell lineage choices in hair follicles by influencing chromatin dynamics during regeneration.

research Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome

119 citations , November 2016 in “American journal of human genetics”

This study reports the discovery of mutations in the PADI3, TGM3, and TCHH genes as molecular genetic causes of uncombable hair syndrome in children, indicating an autosomal-recessive inheritance pattern.

research Emerging Interactions Between Skin Stem Cells and Their Niches

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research Genome-Wide Maps of Histone Modifications Unwind In Vivo Chromatin States of the Hair Follicle Lineage

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This study found that polycomb-group-mediated repression plays a key role in regulating hair follicle stem cell states and lineage progression by distinct mechanisms in adult mouse skin.

research Matrix Metalloproteinase-9 Is Involved in the Regulation of Hair Canal Formation

20 citations , September 2010 in “The journal of investigative dermatology/Journal of investigative dermatology”

This study suggests that MMP-9 plays a significant role in extracellular matrix remodeling during hair canal formation in mice, as indicated by delayed hair shaft emergence and hair canal development in MMP-9 knockout mice.

research Specific Citrullination Causes Assembly of a Globular S100A3 Homotetramer

62 citations , December 2007 in “Journal of biological chemistry/The Journal of biological chemistry”

This study found that enzymatic conversion of Arg-51 in S100A3 protein to citrulline promotes homotetramer assembly, potentially increasing Ca²⁺ binding required for hair cuticular barrier formation.

research Peptidylarginine Deiminase Isoforms Are Differentially Expressed in Anagen Hair Follicles and Other Human Skin Appendages

71 citations , June 2005 in “Journal of Investigative Dermatology”

This study demonstrates that PAD1 and PAD3 are involved in hair follicle differentiation, while PAD1 and PAD2 may play a role in the physiology of sweat glands and arrector pili muscles.

research Defining BMP Functions in the Hair Follicle by Conditional Ablation of BMP Receptor IA

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This study found that BMP receptor IA is crucial for hair progenitor cell differentiation in mice, and its sequential inhibition and activation are necessary to generate a functioning hair shaft.

research Trichohyalin Mechanically Strengthens the Hair Follicle

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138 citations , November 1977 in “Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics”

research Content of Citrulline and Other Amino Acids in Hair Follicle Protein

88 citations , July 1958 in “Nature”

This study reported the first known occurrence of citrulline in an animal protein, specifically in the fibrous protein of hair follicle inner root sheaths.