To determine how ATF4 transcription factor heterodimers regulate gene expression changes in Parkinson’s disease (PD).

Gene expression analysis of substantia nigra from PD patients has identified numerous differentially expressed genes (DEGs) involved in cellular pathways such as mitochondrial function, synapse organization, and macroautophagy. However, how changes in gene expression are regulated remains unknown. ATF4 is a stress-responsive, obligate heterodimeric transcription factor (TF) that has been implicated in PD. Most studies of the role of TFs in disease have focused on identifying changes in TF expression level and correlating that with function. However, we hypothesized that changes in heterodimerization patterns could also result in disease-specific transcriptional deregulation. This project has focused on understanding how ATF4 transcription factor heterodimeric complexes affect PD pathogenesis by altering gene expression.

We focused primarily on a novel TF heterodimer consisting of ATF4 and another stress-responsive TF, CREB3L2. We developed an innovative molecular technique called ChIPmera to identify a large dataset consisting of all possible transcriptional targets of this complex and then compared this dataset with a PD patient-derived gene expression dataset to identify a network of PD-associated DEGs that are also potential targets of the ATF4-CREB3L2 complex. Network analysis was performed to identify cellular pathways whose dysregulation in PD may be mediated by this ATF4 heterodimeric complex.

We identified 255 genes that are both dysregulated in PD and potential transcriptional targets of the ATF4-CREB3L2 TF complex. Network and functional enrichment analysis of these genes identified several clusters associated with different cellular pathways, including those well-known to be dysregulated in PD, such as mitochondrion organization, and less well-studied pathways such as RNA splicing.

These results demonstrate a novel approach for dissecting the link between specific TF complexes, differential gene expression, and cellular dysfunction in PD.