Comprehensively Profiling the Chromatin Architecture of Tissue Restricted Antigen Expression in Thymic Epithelial Cells Over Development

Abstract

Thymic epithelial cells (TEC) effect crucial roles in thymopoiesis including the control of negative thymocyte selection. This process depends on their capacity to express promiscuously genes encoding tissue-restricted antigens. This competence is accomplished in medullary TEC (mTEC) in part by the presence of the transcriptional facilitator AutoImmune REgulator, AIRE. AIRE-regulated gene transcription is marked by repressive chromatin modifications, including H3K27me3. When during TEC development these chromatin marks are established, however, remains unclear. Here we use a comprehensive ChIP-seq dataset of multiple chromatin modifications in different TEC subtypes to demonstrate that the chromatin landscape is established early in TEC differentiation. Much of the chromatin architecture found in mature mTEC was found to be present already over earlier stages of mTEC lineage differentiation as well as in non-TEC tissues. This was reflected by the fact that a machine learning approach accurately classified genes as AIRE-induced or AIRE-independent both in immature and mature mTEC. Moreover, analysis of TEC specific enhancer elements identified candidate transcription factors likely to be important in mTEC development and function. Our findings indicate that the mature mTEC chromatin landscape is laid down early in mTEC differentiation, and that AIRE is not required for large-scale re-patterning of chromatin in mTEC.

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

“…Novel transcript structures were detected in genes of known importance for TEC function, including Foxn1 (Zuklys et al 2016) and Aire (Abramson and Goldfarb 2016) (Supplemental Table 3). Genes that produced transcripts harbouring novel exons or exon skipping events in TEC included Cdx1 , a transcription factor linked with mTEC maturation (Handel et al 2018) (Fig. 2E); Cd80 , a receptor important for interaction with T-cells via CD28 and CTLA4; the MHC class II gene H2-Aa; Mill1 , an MHC class I-like molecule that is known to be expressed on a subpopulation of TEC (Kajikawa et al 2006) (Fig.…”

“…RNA-sequencing data for the 21 peripheral mouse tissues were obtained from the ENCODE project (GSE36025; 8-week old mice, keeping only the colon samples to represent the large intestine). RNA-sequencing from skin epithelial cells (GSM1094285) 59 , cTEC (GSE53111) 5 , and single mature mTEC (GSE114713) 21 shown in Fig. 4 was obtained from the Gene Expression Omnibus (GEO).…”

The contribution of thymic tolerance to central nervous system autoimmunity

“…Error bars show empirical 95% confidence intervals. TRA organ specificity was defined as in [56]. Data was derived from [56,57] induction of cerebral and spinal inflammation by myelin autoantigens, such as myelin oligodendrocyte glycoprotein (MOG), proteolipid protein (PLP) and myelin basic protein (MBP).…”

“…TRA organ specificity was defined as in [56]. Data was derived from [56,57] induction of cerebral and spinal inflammation by myelin autoantigens, such as myelin oligodendrocyte glycoprotein (MOG), proteolipid protein (PLP) and myelin basic protein (MBP). This system has been widely used to model the key features of human MS, albeit with several key clinical and pathophysiological differences between human CNS autoimmunity and EAE [79,80].…”

The presentation of neuroendocrine self‐peptides in the thymus: an essential event for individual life and vertebrate survival

“…The epigenetic regulation of promiscuous gene expression in the thymus is currently under intense investigation . Most probably, these studies might explain in the future the hierarchy in the expression of neuroendocrine self‐peptides belonging to the same family, the absence of parental imprinting of IGF2 transcription in TECs, and control of the immunological mirror of self in the thymus.…”