ZNF750 is a P63 Target Gene That Induces KLF4 to Drive Terminal Epidermal Differentiation

Overview

Journal Dev Cell

Publisher Cell Press

Specialties Cell Biology
Reproductive Medicine

Date 2012 Feb 28

PMID 22364861

Citations 145

Authors

George L Sen

Lisa D Boxer

Dan E Webster

Rose T Bussat

Kun Qu

Brian J Zarnegar

Danielle Johnston

Zurab Siprashvili

Paul A Khavari

Affiliations

Soon will be listed here.

Abstract

Disrupted epidermal differentiation characterizes numerous diseases that impact >25% of the population. In a search for dominant mediators of differentiation, we defined a requirement for ZNF750 in terminal epidermal differentiation. ZNF750 controlled genes mutated in numerous human skin diseases, including FLG, LOR, LCE3B, ALOXE3, and SPINK5. ZNF750 induced progenitor differentiation via an evolutionarily conserved C2H2 zinc finger motif. The epidermal master regulator, p63, bound the ZNF750 promoter and was necessary for its induction. ZNF750 restored differentiation to p63-deficient tissue, suggesting that it acts downstream of p63. A search for functionally important ZNF750 targets via analysis of ZNF750-regulated genes identified KLF4, a transcription factor that activates late epidermal differentiation. ZNF750 binds to KLF4 at multiple sites flanking the transcriptional start site and controls its expression. ZNF750 thus directly links a tissue-specifying factor, p63, to an effector of terminal differentiation, KLF4, and represents a potential future target for disorders of this process.

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References

Teng A, Nair M, Wells J, Segre J, Dai X . Strain-dependent perinatal lethality of Ovol1-deficient mice and identification of Ovol2 as a downstream target of Ovol1 in skin epidermis. Biochim Biophys Acta. 2006; 1772(1):89-95. PMC: 1773004. DOI: 10.1016/j.bbadis.2006.08.012. View

Truong A, Kretz M, Ridky T, Kimmel R, Khavari P . p63 regulates proliferation and differentiation of developmentally mature keratinocytes. Genes Dev. 2006; 20(22):3185-97. PMC: 1635152. DOI: 10.1101/gad.1463206. View

Mills A, Zheng B, Wang X, Vogel H, Roop D, Bradley A . p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature. 1999; 398(6729):708-13. DOI: 10.1038/19531. View

Leech S, Moss C . A current and online genodermatosis database. Br J Dermatol. 2007; 156(6):1115-48. DOI: 10.1111/j.1365-2133.2007.07834.x. View

Koster M, Dai D, Marinari B, Sano Y, Costanzo A, Karin M . p63 induces key target genes required for epidermal morphogenesis. Proc Natl Acad Sci U S A. 2007; 104(9):3255-60. PMC: 1805532. DOI: 10.1073/pnas.0611376104. View

Koster M . p63 in skin development and ectodermal dysplasias. J Invest Dermatol. 2010; 130(10):2352-8. PMC: 2919658. DOI: 10.1038/jid.2010.119. View

Ihrie R, Marques M, Nguyen B, Horner J, Papazoglu C, Bronson R . Perp is a p63-regulated gene essential for epithelial integrity. Cell. 2005; 120(6):843-56. DOI: 10.1016/j.cell.2005.01.008. View

Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson R . p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature. 1999; 398(6729):714-8. DOI: 10.1038/19539. View

Yang C, Hwu W, Yang L, Chung W, Chien Y, Hung C . A promoter sequence variant of ZNF750 is linked with familial psoriasis. J Invest Dermatol. 2008; 128(7):1662-8. DOI: 10.1038/jid.2008.1. View

10.

Truong A, Khavari P . Control of keratinocyte proliferation and differentiation by p63. Cell Cycle. 2007; 6(3):295-9. DOI: 10.4161/cc.6.3.3753. View

11.

Kouwenhoven E, van Heeringen S, Tena J, Oti M, Dutilh B, Alonso M . Genome-wide profiling of p63 DNA-binding sites identifies an element that regulates gene expression during limb development in the 7q21 SHFM1 locus. PLoS Genet. 2010; 6(8):e1001065. PMC: 2924305. DOI: 10.1371/journal.pgen.1001065. View

12.

Crum C, McKeon F . p63 in epithelial survival, germ cell surveillance, and neoplasia. Annu Rev Pathol. 2010; 5:349-71. DOI: 10.1146/annurev-pathol-121808-102117. View

13.

Birnbaum R, Zvulunov A, Hallel-Halevy D, Cagnano E, Finer G, Ofir R . Seborrhea-like dermatitis with psoriasiform elements caused by a mutation in ZNF750, encoding a putative C2H2 zinc finger protein. Nat Genet. 2006; 38(7):749-51. DOI: 10.1038/ng1813. View

14.

Patel S, Xi Z, Seo E, McGaughey D, Segre J . Klf4 and corticosteroids activate an overlapping set of transcriptional targets to accelerate in utero epidermal barrier acquisition. Proc Natl Acad Sci U S A. 2006; 103(49):18668-73. PMC: 1693720. DOI: 10.1073/pnas.0608658103. View

15.

Nestle F, Kaplan D, Barker J . Psoriasis. N Engl J Med. 2009; 361(5):496-509. DOI: 10.1056/NEJMra0804595. View

16.

de Cid R, Riveira-Munoz E, Zeeuwen P, Robarge J, Liao W, Dannhauser E . Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nat Genet. 2009; 41(2):211-5. PMC: 3128734. DOI: 10.1038/ng.313. View

17.

Segre J, Bauer C, Fuchs E . Klf4 is a transcription factor required for establishing the barrier function of the skin. Nat Genet. 1999; 22(4):356-60. DOI: 10.1038/11926. View

18.

Smith F, Irvine A, Terron-Kwiatkowski A, Sandilands A, Campbell L, Zhao Y . Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006; 38(3):337-42. DOI: 10.1038/ng1743. View

19.

Senoo M, Pinto F, Crum C, McKeon F . p63 Is essential for the proliferative potential of stem cells in stratified epithelia. Cell. 2007; 129(3):523-36. DOI: 10.1016/j.cell.2007.02.045. View

20.

Sen G, Reuter J, Webster D, Zhu L, Khavari P . DNMT1 maintains progenitor function in self-renewing somatic tissue. Nature. 2010; 463(7280):563-7. PMC: 3050546. DOI: 10.1038/nature08683. View