Chd4 choreographs self-antigen expression for central immune tolerance

Tomofuji, Yoshihiko; Takaba, Hiroyuki; Suzuki, Hiroshi; Benlaribi, Rayene; Martinez, Cristian David Peña; Abe, Yoshihiro; Morishita, Yasuyuki; Okamura, Tadashi; Taguchi, Azuma; Kodama, Tatsuhiko; Takayanagi, Hiroshi

doi:10.1038/s41590-020-0717-2

Cited by 55 publications

(95 citation statements)

References 67 publications

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“…Furthermore, AIRE-dependent RNAs are preferentially stabilised through the 3′ end processing complex that generates short 3′ UTRs and protects against miRNAmediated degradation [38]. In the mouse, the spectrum of AIRE-driven TRAs is further broadened by cooperation of AIRE with the transcription factor, Fezf2, and the chromatin modulator, Chd4 [39]. On the other hand, the expression of AIRE and its target genes is suppressed by oestrogens, which may explain the gender bias of several autoimmune diseases [40].…”

Section: Aire Expression In the Thymic Medullamentioning

confidence: 99%

“…The second gene identified to drive TRA expression in the thymus is the transcription factor 'forebrain expressed zinc finger 2' (Fezf2) [72]. It is mainly expressed in the brain [73,74], also close to Hassall corpuscles in the human thymus, and in a subset of mTECs, some being AIRE + too [39] (Fig. 1).…”

Section: Fezf2 and Chd4 Expression In Mtecsmentioning

confidence: 99%

“…Fezf2 regulates the expression of about 400 TRAs that are distinct from those regulated by AIRE [34]. About 1000 TRAs are co-regulated by either Fezf2 and AIRE [34] or Fezf2 and Chd4 [39]. Transplantation of Fezf2 −/− thymi into nude mice elicits organ infiltrates and autoantibodies that are different from those in AIRE −/− mice [14,72].…”

Section: Fezf2 and Chd4 Expression In Mtecsmentioning

confidence: 99%

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Thymus and autoimmunity

et al. 2021

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The thymus prevents autoimmune diseases through mechanisms that operate in the cortex and medulla, comprising positive and negative selection and the generation of regulatory T-cells (Tregs). Egress from the thymus through the perivascular space (PVS) to the blood is another possible checkpoint, as shown by some autoimmune/immunodeficiency syndromes. In polygenic autoimmune diseases, subtle thymic dysfunctions may compound genetic, hormonal and environmental cues. Here, we cover (a) tolerance-inducing cell types, whether thymic epithelial or tuft cells, or dendritic, B- or thymic myoid cells; (b) tolerance-inducing mechanisms and their failure in relation to thymic anatomic compartments, and with special emphasis on human monogenic and polygenic autoimmune diseases and the related thymic pathologies, if known; (c) polymorphisms and mutations of tolerance-related genes with an impact on positive selection (e.g. the gene encoding the thymoproteasome-specific subunit, PSMB11), promiscuous gene expression (e.g. AIRE, PRKDC, FEZF2, CHD4), Treg development (e.g. SATB1, FOXP3), T-cell migration (e.g. TAGAP) and egress from the thymus (e.g. MTS1, CORO1A); (d) myasthenia gravis as the prototypic outcome of an inflamed or disordered neoplastic ‘sick thymus’.

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Section: Aire Expression In the Thymic Medullamentioning

confidence: 99%

Section: Fezf2 and Chd4 Expression In Mtecsmentioning

confidence: 99%

Section: Fezf2 and Chd4 Expression In Mtecsmentioning

confidence: 99%

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Thymus and autoimmunity

et al. 2021

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“…A putative second mechanism enabling PGE in TECs seemingly employs the neuronal transcription factor Fezf2, which recognizes a number of TRA-encoding loci different from those controlled by AIRE [71]. Interestingly, both AIRE and Fezf2 depend for the transcription of some but not all of their target genes on the ubiquitously expressed chromatin remodelling enzyme Chd4 [72]. This common dependence on a molecule that recognizes repressive histone marks suggests that both AIRE and Fezf2 take advantage of comparable molecular mechanisms for their activity.…”

Section: Autoimmunity As a Failure Of Thymus-dependent Self-tolerancementioning

confidence: 99%

The thymus and the science of self

Geenen

2021

Semin Immunopathol

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The conventional perception asserts that immunology is the science of ‘discrimination’ between self and non-self. This concept is however no longer tenable as effector cells of the adaptive immune system are first conditioned to be tolerant to the body’s own antigens, collectively known as self until now. Only then attain these effectors the responsiveness to non-self. The acquisition of this essential state of tolerance to self occurs for T cells in the thymus, the last major organ of our body that revealed its intricate function in health and disease. The ‘thymus’ as an anatomical notion was first notably documented in Ancient Greece although our present understanding of the organ’s functions was only deciphered commencing in the 1960s. In the late 1980s, the thymus was identified as the site where clones of cells reactive to self, termed ‘forbidden’ thymocytes, are physically depleted as the result of a process now known as negative selection. The recognition of this mechanism further contributed to the belief that the central rationale of immunology as a science lies in the distinction between self and non-self. This review will discuss the evidence that the thymus serves as a unique lymphoid organ able to instruct T cells to recognize and be tolerant to harmless self before adopting the capacity to defend the body against potentially injurious non-self-antigens presented in the context of different challenges from infections to exposure to malignant cells. The emerging insight into the thymus’ cardinal functions now also provides an opportunity to exploit this knowledge to develop novel strategies that specifically prevent or even treat organ-specific autoimmune diseases.

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“…This process of “promiscuous gene expression” (PGE), is essential for the avoidance of autoimmunity and involves transcription of approximately 89% of protein-coding genes by the TEC population (Sansom et al 2014; Abramson and Anderson 2017). The mechanisms by which TEC defy developmental and tissue-specific transcriptional controls to achieve PGE are only incompletely deciphered (Abramson and Goldfarb 2016), although the AutoImmune Regulator (Aire) (Sansom et al 2014) and the transcription factor Fezf2 (Takaba et al 2015) together with the chromatin remodeler Chd4 (Tomofuji et al 2020) are known to enable PGE. Comprehensiveness of self-representation by TEC cannot, however, be measured by gene number alone because self-peptidome diversity is elaborated by alternative mRNA splicing (Matera and Wang 2014), expression of “untranslated” regions (Starck and Shastri 2016), RNA-editing (Danan-Gotthold et al 2016), proteasome mediated splicing (Granados et al 2015) and post-translational modifications (Raposo et al 2018).…”

Section: Introductionmentioning

confidence: 99%

A transcriptomic census reveals that Rbfox contributes to a broad but selective recapitulation of peripheral tissue splicing patterns in the thymus

Jansen

Shikama-Dorn

Attar

et al. 2020

Preprint

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Thymic epithelial cells (TEC) guide selection of a T-cell repertoire that is reactive to pathogens but tolerant to self. While this process is known to involve the promiscuous expression of virtually the entire protein-coding gene repertoire by TEC, the extent to which these cells reproduce peripheral isoform structures is unknown. We performed a transcriptomic investigation of transcript structures and splicing factor expression in medullary TEC and 21 peripheral tissues. Our results indicate that TEC re-use a small number of peripheral splicing factors to recreate a limited subset of the peripheral splice isoform repertoire. We found, for example, that TEC lacked both neuronal micro-exons and the splicing factor, Srrm4, which promotes their inclusion. We demonstrate a functional role for the Rbfox splicing factors in promoting medullary TEC development and the alternative splicing of promiscuously expressed genes. Our findings have implications for understanding autoimmune diseases and the development of antigen-specific immunotherapies.

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Chd4 choreographs self-antigen expression for central immune tolerance

Cited by 55 publications

References 67 publications

Thymus and autoimmunity

Thymus and autoimmunity

The thymus and the science of self

A transcriptomic census reveals that Rbfox contributes to a broad but selective recapitulation of peripheral tissue splicing patterns in the thymus

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