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Exploring Transcript divergency in a type I diabetes in vitro model using long read RNA sequencing

Lienard, Julia (2025) BINP50 20251
Degree Projects in Bioinformatics
Popular Abstract
Rare divergent RNAs in disease

In human cells, genes are transcribed into an RNA before being translated into a protein, but first its structure under strict regulation undergoes changes called RNA splicing. Premature RNAs are organized in exon and intron units, where the latter are removed, to join exons together in the mature RNA. However, a variation of exon/intron combination can occur via an alternative splicing program or due to rare random errors, resulting in different RNA isoforms. Recent evidence suggests that occurrence of rare erroneous RNA (called in this project Transcript Divergency) increases under cellular stress and could have a biological relevance. This was explored in the current project, using long-read RNA... (More)
Rare divergent RNAs in disease

In human cells, genes are transcribed into an RNA before being translated into a protein, but first its structure under strict regulation undergoes changes called RNA splicing. Premature RNAs are organized in exon and intron units, where the latter are removed, to join exons together in the mature RNA. However, a variation of exon/intron combination can occur via an alternative splicing program or due to rare random errors, resulting in different RNA isoforms. Recent evidence suggests that occurrence of rare erroneous RNA (called in this project Transcript Divergency) increases under cellular stress and could have a biological relevance. This was explored in the current project, using long-read RNA sequencing, in the context of the pancreatic autoimmune disease, type I diabetes.

The study used one of the most recent long-read RNA sequencing technologies allowing high throughput data and low sequencing errors for the two sample groups (Control and Stress pancreatic cells). First, RNA isoforms were investigated between the two samples, based on their structure which either corresponded to the reference RNA for the gene, or showed diverse variations. These variations were further segregated into different groups and the overall distribution of RNAs in these categories appeared highly similar between the samples.
Then, gene expression analysis revealed that stressed pancreatic cells expressed genes involved in antigen presentation, including self-antigens, a condition which may favor development of autoreactive immune cells.

The second part of the project focused on exploring Transcript Divergency (TD), illustrated in the Figure (from Mónzo et al. Genome Research 2025). TD was evaluated using two distinct approaches, based on the RNA isoform subgroups that did not correspond to the reference: incomplete match or with sufficient variations to define novel isoforms.
Divergent RNA isoforms increase in disease
Currently no analytical tool exists for the precise study of TD and therefore this project employed explorative metrics. By either using incomplete match- or novel RNA isoforms to estimate TD, we could observe an increased number of rare divergent isoforms in pancreatic cells under stress. This result thus supports the hypothesis that subsequent erroneous derived proteins in stressed pancreatic cells may contribute to the emergence of autoreactive immune cells and onset of type I diabetes.

In this project, we could show the feasibility of using long-read sequencing for the detection of TD, generating data suggesting that its occurrence is increased under stress. Detection of these rare isoforms underscores the complexity of human gene expression, which highlights the need for continued research to fully elucidate this process.

Master’s Degree Project in Bioinformatics 30 credits 2025
Department of Biology, Lund University

Advisor: Ana Conesa
Institute for Integrative Systems Biology, Valencia, Spain (Less)
Please use this url to cite or link to this publication:
author
Lienard, Julia
supervisor
organization
course
BINP50 20251
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
9215064
date added to LUP
2025-11-07 11:31:11
date last changed
2025-11-07 11:31:11
@misc{9215064,
  author       = {{Lienard, Julia}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{Exploring Transcript divergency in a type I diabetes in vitro model using long read RNA sequencing}},
  year         = {{2025}},
}