Transcript Isoform Variation Associated with Cytosine Modification in Human Lymphoblastoid Cell Lines

Area of Science:

• Epigenetics
• Genomics
• Molecular Biology

Background:

• Cytosine modification on DNA varies between individuals and may correlate with gene expression.
• The specific impact of cytosine modification on interindividual transcript isoform variation (TIV) is not well understood.

Purpose of the Study:

• To investigate the extent of cytosine modification-specific TIV in human lymphoblastoid cell lines (LCLs).
• To explore the relationship between cytosine modification, gene expression, and regulatory elements.
• To determine the mechanisms underlying TIV, such as alternative splicing or transcription termination.

Main Methods:

• Analysis of cytosine modification-specific TIV in LCLs from European and African ancestries.
• Correlation analysis between TIV-associated cytosine modifications and gene expression levels.
• Examination of CpG site locations relative to transcript initiation, transcription factor binding, histone modification, and splicing sites.
• Comparison of LCL-derived TIVs with data from The Cancer Genome Atlas (TCGA).

Main Results:

• Cytosine modification-specific TIVs were detected in 17% of analyzed genes.
• Forty-five percent of TIV-associated modifications correlated with gene expression, often at transcript initiation sites.
• Thirty-three percent of TIV-associated modifications affected specific exons, linked to splicing or termination sites.
• Cytosine modification and genetic regulation of TIV showed shared targets but independent effects.
• TIVs exhibited developmental dependency and were enriched in cancer and metabolic disorder pathways.

Conclusions:

• Cytosine modification variation significantly impacts the transcript isoform spectrum, more so than overall transcript abundance.
• Epigenetic factors, specifically cytosine modification-driven TIV, contribute to disease pathogenesis.
• The findings highlight the role of epigenetic regulation in cellular function and disease susceptibility.