Intronic regulation of Aire expression by Jmjd6 for self-tolerance induction in the thymus

Abstract

The thymus has spatially distinct microenvironments, the cortex and the medulla, where the developing T-cells are selected to mature or die through the interaction with thymic stromal cells. To establish the immunological self in the thymus, medullary thymic epithelial cells (mTECs) express diverse sets of tissue-specific self-antigens (TSAs). This ectopic expression of TSAs largely depends on the transcriptional regulator Aire, yet the mechanism controlling Aire expression itself remains unknown. Here, we show that Jmjd6, a dioxygenase that catalyses lysyl hydroxylation of splicing regulatory proteins, is critical for Aire expression. Although Jmjd6 deficiency does not affect abundance of Aire transcript, the intron 2 of Aire gene is not effectively spliced out in the absence of Jmjd6, resulting in marked reduction of mature Aire protein in mTECs and spontaneous development of multi-organ autoimmunity in mice. These results highlight the importance of intronic regulation in controlling Aire protein expression.

PCAF-mediated acetylation of transcriptional factor HOXB9 suppresses lung adenocarcinoma progression by targeting oncogenic protein JMJD6

“…JMJD6 catalyzes the hydroxylation of p53 to regulate colon cancer progression (31). Recently, JMJD6 was reported to regulate Aire expression, which is critical for the establishment of immunological self-tolerance in the thymus (40). However, how JMJD6 is regulated remains elusive.…”

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

“…HIPK2 was recently shown to also modulate the development of thymic tuft cells, which represent a subset of thymic epithelial cells that rely on the taste chemosensory molecule TRPM5 for their thymic function and pass through an Aire‐dependent phase for their thymic development . Moreover, the lysyl‐hydroxylase Jmjd6 (Jumonji domain‐containing protein 6) affects splicing of intron 2 of the Aire gene and is required for expression of mature Aire in mTECs, and Dgcr8 (DiGeorge syndrome critical region gene 8) is important for accumulation of Aire‐expressive mTECs in the thymus . Recent work from Herzig et al further demonstrated a very complex method of Aire expression regulation resulting from positive and negative mechanisms and the coordinated effort of multiple transcription factors, Irf4, Irf8, Tbx21, Tcf7, and Ctcfl.…”

Insights into immune tolerance from AIRE deficiency

“…For example, the recent characterization of the first cis-regulatory element of Aire represents a major conceptual advance [30,31]. Coding elements that affect mouse Aire expression include Jmjd6 , Sirt1 , Hipk2 , Dgcr8 , and Fbxo3 (Table 2) [32–36]. Importantly, the recent identification of Fezf2 as a key regulator of Aire-independent TSA expression in mTECs underscores that TSA representation in the thymus is likely to involve yet to be discovered factors that cooperate with AIRE and may help explain organ-specific phenotypic expressions of APS-1 or, conceivably, in patients with monogenic or multigenic autoimmune diseases [37].…”