Indispensable epigenetic control of thymic epithelial cell development and function by polycomb repressive complex 2

Thomas Barthlott, Adam E. Handel, Hong Ying Teh, Rushika C. Wirasinha, Katrin Hafen, Saulius Žuklys, Benoit Roch, Stuart H. Orkin, Jean-Pierre Villartay, Stephen R. Daley and Georg A. Holländer ()
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Thomas Barthlott: University of Basel
Adam E. Handel: University of Oxford
Hong Ying Teh: University of Basel
Rushika C. Wirasinha: Monash University
Katrin Hafen: University of Basel
Saulius Žuklys: University of Basel
Benoit Roch: Université de Paris, Imagine Institute
Stuart H. Orkin: Harvard Medical School, and Howard Hughes Medical Institute
Jean-Pierre Villartay: Université de Paris, Imagine Institute
Stephen R. Daley: Monash University
Georg A. Holländer: University of Basel

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract Thymic T cell development and T cell receptor repertoire selection are dependent on essential molecular cues provided by thymic epithelial cells (TEC). TEC development and function are regulated by their epigenetic landscape, in which the repressive H3K27me3 epigenetic marks are catalyzed by polycomb repressive complex 2 (PRC2). Here we show that a TEC-targeted deficiency of PRC2 function results in a hypoplastic thymus with reduced ability to express antigens and select a normal repertoire of T cells. The absence of PRC2 activity reveals a transcriptomically distinct medullary TEC lineage that incompletely off-sets the shortage of canonically-derived medullary TEC whereas cortical TEC numbers remain unchanged. This alternative TEC development is associated with the generation of reduced TCR diversity. Hence, normal PRC2 activity and placement of H3K27me3 marks are required for TEC lineage differentiation and function and, in their absence, the thymus is unable to compensate for the loss of a normal TEC scaffold.

Date: 2021
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DOI: 10.1038/s41467-021-24158-w

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