Inflammatory signaling differentially changes chromatin accessibility and gene expression of the PD-associated kinase LRRK2 between human and mice [snRNA-Seq human]

The genomic locus that encodes the Leucine-rich repeat kinase 2 (LRRK2) gene is highly pleomorphic, being associated with both Parkinson’s disease (PD) and Crohn’s disease (CD). As well as coding variants that are associated with risk of PD and CD and act as gain of function kinase mutations increasing phosphorylation of RAB substrates, non-coding variants in the promoter region of LRRK2 increase expression of the gene, notably in immune cells. If regulation of LRRK2 expression is a causal contributor to age-related diseases, it would therefore be important to understand the mechanism(s) by which LRRK2 is regulated, particularly in the context of inflammation. We were able to show that interferon-ɣ exposure induces robust LRRK2 activation in human iPSC-derived microglia through mechanisms that involve signaling of the Janus-activated Kinase complex to phosphorylate STAT1 which then binds to the LRRK2 promoter and is associated with remodeling of chromatin structure in this genomic locus. Additional regulation includes the stress-induced transcription factor and long non-coding RNA encoded at the same locus, resulting in enhanced LRRK2 mRNA levels. However, we were unable to demonstrate any induction of Lrrk2 mRNA in the mouse brain but could show evidence of the same effect in acutely cultured human brain slices. These divergent results across species are resolved by the demonstration the introduction of a human bacterial artificial chromosome transgene into the mouse genome can then recapitulate sensitivity to interferon-ɣ in microglia. These results demonstrate that there are differences between species in how genes associated with human diseases are regulated and provide important information that should be incorporated in disease modeling.