Fig. 9.

A proposed model of a LINC00844-mediated regulatory network that influences DME and NR gene expression. Our data showed that LINC00844 is a lncRNA responsive to APAP-induced hepatotoxicity and regulates the expression of CYP3A4, CYP2E1, SULT2A1, PXR, and HNF4α. PXR and HNF4α have been shown to transactivate CYP3A4, CYP2E1, and SULT2A1, while HNF4α can also activate PXR. LINC00844 interacts with hsa-miR-486-5p and functionally antagonizes hsa-miR-486-5p as a miRNA sponge to protect SULT2A1 from hsa-miR-486-5p-mediated gene suppression. Also, hsa-miR-486-5p indirectly regulates the expression of CYP3A4, CYP2E1, PXR, and HNF4α via LINC00844. The Genecards database shows the LINC00844 gene has response elements for 15 transcription factors including HNF4α (dotted line), which has been shown to respond to xenobiotic stimuli such as drugs and diet. Solid lines indicate regulation paths newly demonstrated in this study; dashed lines indicate regulation paths that are previously known. All lines are in the same colors as the corresponding regulatory modules/factors