Ying Lyu1,8, Yinglu Guan1,8, Lisa Deliu1, Ericka Humphrey1, Joanna K. Frontera1, Youn Joo Yang1, Daniel Zamler1, Kun Hee Kim2, Vakul Mohanty2, Kevin Jin1,3, Virginia Liu1,3, Jinzhuang Dou2, Lucas J. Veillon2, Shwetha V. Kumar2, Philip L. Lorenzi2, Yang Chen1, Kathleen M. McAndrews1, Sergei Grivennikov4,5, Xingzhi Song6, Jianhua Zhang6, Yuanxin Xi2, Jing Wang2, Ken Chen2, Priyadharsini Nagarajan7 and Yejing Ge1 1Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; 2Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; 3Rice University, Houston, Texas 77005, USA; 4Department of Medicine, Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA; 5Department of Biomedical Sciences, Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA; 6Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; 7Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA Corresponding author: yge1mdanderson.org

↵8 These authors contributed equally to this work.

Abstract

Stem cells are fundamental units of tissue remodeling whose functions are dictated by lineage-specific transcription factors. Home to epidermal stem cells and their upward-stratifying progenies, skin relies on its secretory functions to form the outermost protective barrier, of which a transcriptional orchestrator has been elusive. KLF5 is a Krüppel-like transcription factor broadly involved in development and regeneration whose lineage specificity, if any, remains unclear. Here we report KLF5 specifically marks the epidermis, and its deletion leads to skin barrier dysfunction in vivo. Lipid envelopes and secretory lamellar bodies are defective in KLF5-deficient skin, accompanied by preferential loss of complex sphingolipids. KLF5 binds to and transcriptionally regulates genes encoding rate-limiting sphingolipid metabolism enzymes. Remarkably, skin barrier defects elicited by KLF5 ablation can be rescued by dietary interventions. Finally, we found that KLF5 is widely suppressed in human diseases with disrupted epidermal secretion, and its regulation of sphingolipid metabolism is conserved in human skin. Altogether, we established KLF5 as a disease-relevant transcription factor governing sphingolipid metabolism and barrier function in the skin, likely representing a long-sought secretory lineage-defining factor across tissue types.

Received April 14, 2022. Accepted August 15, 2022.