- Decoding Agc1 deficiency: bioinformatics approaches to unveil the functional implications of Slc25a12 on the transcriptome and epigenome
- Balboni, Nicola <1995>
Subject
- BIO/18 Genetica
Description
- In the brain, mutations in SLC25A12 gene encoding AGC1 cause an ultra-rare genetic disease reported as a developmental and epileptic encephalopathy associated with global cerebral hypomyelination. Symptoms of the disease include diffused hypomyelination, arrested psychomotor development, severe hypotonia, seizures and are common to other neurological and developmental disorders. Amongst the biological components believed to be most affected by AGC1 deficiency are oligodendrocytes, glial cells responsible for myelination. Recent studies (Poeta et al, 2022) have also shown how altered levels of transcription factors and epigenetic modifications greatly affect proliferation and differentiation in oligodendrocyte precursor cells (OPCs). In this study we explore the transcriptomic landscape of Agc1 in two different system models: OPCs silenced for Agc1 and iPSCs from human patients differentiated to neural progenitors. Analyses range from differential expression analysis, alternative splicing, master regulator analysis. ATAC-seq results on OPCs were integrated with results from RNA-Seq to assess the activity of a TF based on the accessibility data from its putative targets, which allows to integrate RNA-Seq data to infer their role as either activators or repressors. All the findings for this model were also integrated with early data from iPSCs RNA-seq results, looking for possible commonalities between the two different system models, among which we find a downregulation in genes encoding for SREBP, a transcription factor regulating fatty acids biosynthesis, a key process for myelination which could explain the hypomyelinated state of patients. We also find that in both systems cells tend to form more neurites, likely losing their ability to differentiate, considering their progenitor state. We also report several alterations in the chromatin state of cells lacking Agc1, which confirms the hypothesis for which Agc1 is not a disease restricted only to metabolic alterations in the cells, but there is a profound shift of the regulatory state of these cells.
Date
- 2024-04-08
- info:eu-repo/date/embargoEnd/2026-01-01
Type
- Doctoral Thesis
- PeerReviewed
Format
- application/pdf
Identifier
urn:nbn:it:unibo-30146
Balboni, Nicola (2024) Decoding Agc1 deficiency: bioinformatics approaches to unveil the functional implications of Slc25a12 on the transcriptome and epigenome, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Biologia cellulare e molecolare