Genome-wide transcriptome analysis for detecting lncRNAs involved in human fatty liver disease development

Supervisors

Biljana Atanasovska / Jingyuan Fu

Background

Long noncoding RNAs (lncRNAs) have been shown to cover a significant portion of the noncoding transcriptome in mammalian genome. These transcripts are not coding for proteins, are longer than 200 nucleotides, have tissue specific expression and are important regulators of gene expression. It has been found that the majority of disease- associated genetic variants are located outside of protein-coding regions where they seems to affect regions that control transcription (promoters, enhancers) and non-coding RNAs that also can influence gene expression. Furthermore, an increasing number of studies have shown that lncRNAs can be involved in various biological processes and their dysregulation can underlie a number of complex human diseases. However, the role of lincRNAs in liver pathology and overall mechanism remain largely unknown.
The association analysis have shown that coding genes play a key role in development and progression of NAFLD by interacting with environmental factors but the molecular mechanisms underlying these associations between gene variants and progressive liver disease remain unknown.
Our hypothesis is that lncRNAs might have a role in these molecular mechanisms and therefore can significantly contribute to a progression of liver diseases including non- alcoholic steatohepatitis (NASH).

Materials and methods

In order to obtain more comprehensive information on long non-coding RNAs in the context of NASH, we sequenced ~40 million RNA reads per sample (range 35-49 million reads). Liver biopsies of 16 morbidly obese patients without non-alcoholic fatty liver disease (NAFLD), 9 morbid obese patients with NAFLD but not NASH, and 35 morbidly obese patients with NASH have been selected for analysis.

Aim

With this data, we aim to identify differences in expression of lncRNAs between patients with and without NASH. However, only ~38% of the (exonic) reads were aligned to the known genes in the human genome and ~50% of the reads were mapped in an intronic region. Therefore, we are interested in specific regions where the candidate ncRNAs are located and would like to investigate different splice variant and isoform abundance.