Developmentally dynamic chromatin state at loci regulating organ crosstalk by remote sensing and signaling

Interorgan communication, metabolite regulation and drug handling require fine-tuned small molecule transport across membranes. The Remote Sensing and Signaling (RSS) theory, which has found applicability in chronic kidney disease and uric acid disorders, emphasizes the central role of solute carrier (SLC) and ATP-binding cassette (ABC) transporters, enzymes and transcription factors in organ crosstalk. Based on prior network biology studies, ~ 1000 protein-coding genes are predicted to mediate RSS. This gene set largely overlaps with genes that are important for absorption, digestion, metabolism and excretion (ADME) of small molecules. However, it is not known how epigenetic regulation of these loci changes during the development of the liver and kidney, which control the small molecule composition of the blood, or the brain, whose physiology relies upon this process. Epigenetic regulation of these genes is also critical for understanding pharmacokinetics.

We profiled chromatin state at 1034 RSS/ADME genes in the mouse kidney, liver and brain at the embryonic and adult stages. Using the high-resolution chromatin mapping method CUT&RUN, we examined the activating histone modifications H3K4me3, H3K27ac and H3K9ac, and the repressive modification H3K27me3. Activating modifications were most dynamic at the chromatin level in the liver and least dynamic in the brain. Acetylated histone modifications were more dynamic overall than methylation marks in all three tissues. Hierarchical clustering demonstrated that a subset of RSS/ADME genes undergoes a coordinated program of activation during kidney and liver development that correlates with changes in transcript abundance.

Defining the changes in chromatin that occur after birth within this gene set provides insight into tissue-specific regulation of RSS. Our findings carry implications for how the body acquires autonomous functionality through organ crosstalk mediated by transport of endogenous small molecules. Given their critical roles in ADME as well as handling of exogenous toxins, medications and metabolites derived from the gut microbiome, our analysis has ramifications for both precision pharmacology and diseases such as chronic kidney disease, metabolic syndrome and gout, in which dysregulation of RSS drives pathophysiology.