Transcriptomic diversity in human medullary thymic epithelial cells.

Area of Science:

• Immunology and Molecular Biology
• Transcriptomics and Gene Expression

Background:

• Central T cell tolerance in the thymus relies on medullary thymic epithelial cells (mTECs) presenting peripheral self-epitopes.
• Promiscuous gene expression (pGE) in mTECs generates transcriptomic diversity through mechanisms like alternative splicing and retroelement expression.

Purpose of the Study:

• To comprehensively map genome-wide transcript expression in immature and mature human mTECs.
• To elucidate the roles of non-canonical transcript initiation, alternative splicing, and endogenous retroelements (EREs) in mTEC transcriptomic diversity.

Main Methods:

• High-throughput 5' cap and RNA sequencing were employed to analyze transcriptomes of immature and mature human mTECs.
• Bioinformatic analyses were used to assess splicing entropy, transcript initiation, and ERE expression patterns.

Main Results:

• Both immature and mature mTECs exhibit high splicing entropy, potentially influenced by peripheral splicing factors.
• mTEC maturation is associated with increased global transcript mis-initiation and upregulation of long terminal repeat retrotransposons (EREs).
• EREs are frequently located near differentially expressed genes, suggesting a functional role in mTEC gene regulation.

Conclusions:

• This study provides a detailed map of transcriptomic diversity in the healthy human thymus, highlighting novel contributors to mTEC heterogeneity.
• The findings enhance our understanding of the molecular mechanisms underlying mTEC function in establishing central T cell tolerance.
• This resource may aid in identifying epitopes relevant to autoimmunity and tumor antigen recognition.