Identification of an Intronic Regulatory Element Necessary for Tissue-Specific Expression of in Thymic Epithelial Cells

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2019 Jun 28

PMID 31243087

Citations 13

Authors

Brian M Larsen

Jennifer E Cowan

Yueqiang Wang

Yu Tanaka

Yongge Zhao

Benjamin Voisin

Michael G Constantinides

Keisuke Nagao

Yasmine Belkaid

Parirokh Awasthi

Yousuke Takahama

Avinash Bhandoola

Affiliations

Soon will be listed here.

Abstract

The thymus is critical for the establishment of the adaptive immune system and the development of a diverse T cell repertoire. T cell development depends upon cell-cell interactions with epithelial cells in the thymus. The thymus is composed of two different types of epithelial cells: cortical and medullary epithelial cells. Both of these express and critically depend on the transcription factor is also expressed in the hair follicle, and disruption of function in mice results in severe thymic developmental defects and the hairless (nude) phenotype. Despite its importance, little is known about the direct regulation of expression. In this study, we identify a -regulatory element (RE) critical for expression of in mouse thymic epithelial cells but dispensable for expression in hair follicles. Analysis of chromatin accessibility, histone modifications, and sequence conservation identified regions within the first intron of that possessed the characteristics of REs. Systematic knockout of candidate regions lead us to identify a 1.6 kb region that, when deleted, results in a near total disruption of thymus development. Interestingly, expression and function in the hair follicle were unaffected. RNA fluorescent in situ hybridization showed a near complete loss of mRNA expression in the embryonic thymic bud. Our studies have identified a genomic RE with thymic-specific control of gene expression.

Citing Articles

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Topoisomerase 1 is required for the development and function of thymus.

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Hair Follicle Transcriptome Analysis Reveals Differentially Expressed Genes That Regulate Wool Fiber Diameter in Angora Rabbits.

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Thymus Functionality Needs More Than a Few TECs.

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References

Lee D, Prowse D, Brissette J . Association between mouse nude gene expression and the initiation of epithelial terminal differentiation. Dev Biol. 1999; 208(2):362-74. DOI: 10.1006/dbio.1999.9221. View

Tilloy F, Treiner E, Park S, Garcia C, Lemonnier F, de la Salle H . An invariant T cell receptor alpha chain defines a novel TAP-independent major histocompatibility complex class Ib-restricted alpha/beta T cell subpopulation in mammals. J Exp Med. 1999; 189(12):1907-21. PMC: 2192962. DOI: 10.1084/jem.189.12.1907. View

Anderson G, Jenkinson E . Lymphostromal interactions in thymic development and function. Nat Rev Immunol. 2002; 1(1):31-40. DOI: 10.1038/35095500. View

Cunliffe V, Furley A, Keenan D . Complete rescue of the nude mutant phenotype by a wild-type Foxn1 transgene. Mamm Genome. 2002; 13(5):245-52. DOI: 10.1007/s00335-001-3079-6. View

Xu P, Zheng W, Laclef C, Maire P, Maas R, Peters H . Eya1 is required for the morphogenesis of mammalian thymus, parathyroid and thyroid. Development. 2002; 129(13):3033-44. PMC: 3873877. DOI: 10.1242/dev.129.13.3033. View

Bennett A, Farley A, Blair N, Gordon J, Sharp L, Blackburn C . Identification and characterization of thymic epithelial progenitor cells. Immunity. 2002; 16(6):803-14. DOI: 10.1016/s1074-7613(02)00321-7. View

Balciunaite G, Keller M, Balciunaite E, Piali L, Zuklys S, Mathieu Y . Wnt glycoproteins regulate the expression of FoxN1, the gene defective in nude mice. Nat Immunol. 2002; 3(11):1102-8. DOI: 10.1038/ni850. View

Adriani M, Martinez-Mir A, Fusco F, Busiello R, Frank J, Telese S . Ancestral founder mutation of the nude (FOXN1) gene in congenital severe combined immunodeficiency associated with alopecia in southern Italy population. Ann Hum Genet. 2004; 68(Pt 3):265-8. DOI: 10.1046/j.1529-8817.2004.00091.x. View

Benlagha K, Wei D, Veiga J, Teyton L, Bendelac A . Characterization of the early stages of thymic NKT cell development. J Exp Med. 2005; 202(4):485-92. PMC: 2212852. DOI: 10.1084/jem.20050456. View

10.

Bleul C, Boehm T . BMP signaling is required for normal thymus development. J Immunol. 2005; 175(8):5213-21. DOI: 10.4049/jimmunol.175.8.5213. View

11.

Zou D, Silvius D, Davenport J, Grifone R, Maire P, Xu P . Patterning of the third pharyngeal pouch into thymus/parathyroid by Six and Eya1. Dev Biol. 2006; 293(2):499-512. PMC: 3882147. DOI: 10.1016/j.ydbio.2005.12.015. View

12.

Bleul C, Corbeaux T, Reuter A, Fisch P, Monting J, Boehm T . Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature. 2006; 441(7096):992-6. DOI: 10.1038/nature04850. View

13.

Heintzman N, Stuart R, Hon G, Fu Y, Ching C, Hawkins R . Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet. 2007; 39(3):311-8. DOI: 10.1038/ng1966. View

14.

Murata S, Sasaki K, Kishimoto T, Niwa S, Hayashi H, Takahama Y . Regulation of CD8+ T cell development by thymus-specific proteasomes. Science. 2007; 316(5829):1349-53. DOI: 10.1126/science.1141915. View

15.

Chen L, Xiao S, Manley N . Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner. Blood. 2008; 113(3):567-74. PMC: 2628364. DOI: 10.1182/blood-2008-05-156265. View

16.

Visel A, Blow M, Li Z, Zhang T, Akiyama J, Holt A . ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature. 2009; 457(7231):854-8. PMC: 2745234. DOI: 10.1038/nature07730. View

17.

Cheng L, Guo J, Sun L, Fu J, Barnes P, Metzger D . Postnatal tissue-specific disruption of transcription factor FoxN1 triggers acute thymic atrophy. J Biol Chem. 2009; 285(8):5836-47. PMC: 2820809. DOI: 10.1074/jbc.M109.072124. View

18.

Sun L, Guo J, Brown R, Amagai T, Zhao Y, Su D . Declining expression of a single epithelial cell-autonomous gene accelerates age-related thymic involution. Aging Cell. 2010; 9(3):347-57. PMC: 2894280. DOI: 10.1111/j.1474-9726.2010.00559.x. View

19.

Noonan J, McCallion A . Genomics of long-range regulatory elements. Annu Rev Genomics Hum Genet. 2010; 11:1-23. DOI: 10.1146/annurev-genom-082509-141651. View

20.

Heinz S, Benner C, Spann N, Bertolino E, Lin Y, Laslo P . Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. 2010; 38(4):576-89. PMC: 2898526. DOI: 10.1016/j.molcel.2010.05.004. View