Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome
Background: Growing evidence has recommended that Type I Interferon (I-IFN) plays a possible role within the pathogenesis of Lower Syndrome (DS). The work investigates the actual purpose of MX1, an effector gene of I-IFN, in DS-connected transcriptional regulation and phenotypic modulation.
Methods: We performed assay for transposase-accessible chromatin rich in-throughout sequencing (ATAC-seq) look around the difference of chromatin ease of access between DS derived amniocytes (DSACs) and controls. Then we combined the annotated differentially expressed genes (DEGs) and enriched transcriptional factors (TFs) individuals promoter region from ATAC-seq results using the DEGs in RNA-seq, to recognize key genes and pathways involved with alterations of biological processes and pathways in DS.
Results: Binding motif analysis demonstrated a substantial rise in chromatin ease of access of genes associated with neural cell function, amongst others, in DSACs, that is mainly controlled by people from the activator protein-1 (AP-1) transcriptional factor family. Further studies established that MX Dynamin Like GTPase 1 (MX1), defined among the key effector genes of I-IFN, is really a critical upstream regulator. Its overexpression caused expression of AP-1 TFs and mediated inflammatory response, thus resulting in decreased cellular viability of DS cells. Furthermore, treatment with specific AP-1 inhibitor T-5224 improved DS-connected phenotypes in DSACs.
Conclusions: This research shows that MX1-mediated AP-1 activation is partly accountable for cellular disorder of DS. T-5224 effectively ameliorated DS-connected phenotypes in DSACs, suggesting it as being a possible treatment choice for DS patients.