## 2 Results
### En Bloc and Multi-Loci Up-Regulation of the Hexanoate Pathway and Cannabinoid Biosynthesis  
The regulation of the hexanoate pathway was distinct from the MEP and MVA pathways in two ways: (i) the en bloc transcriptional up-regulation of all seven steps in the pathway, which is frequently achieved via (ii) numerous gene loci (Figure 3a). Such multi-loci regulated enzymes included linoleicate lipoxygenase (LOX), ALDH, AAE, and OAC, with their log\({}_{2}\) FC values of gene expression ranging from 2.5 to 7.6 (5 loci), 4.8 to 12 (3 loci), 2.1 to 8.1 (3 loci), and 9.1 to 9.2 (2 loci), respectively. This mode of regulation was also found with enzymes directly involved in cannabinoid biosynthesis (Figure 3a). For example, the aromatic premyltransferases (APT) and THCA synthase (THCAS) enzyme genes showed respective log\({}_{2}\) FC values ranging between 5.1 and 9.9 (5 loci), and 7.7 and 91 (2 loci). The en bloc and multigene loci mode of regulation shared by both pathways can be ascribed to their more straightforward role in cannabinoid production in the trichomes compared to the MEP and MVA pathways. Figure 3: Distinct mode of transcriptional regulation for secondary metabolite biosynthetic pathways. (**a**) M-D plot of DEGs (trichomes versus stem tissue) in the MEP, MVA, hexanoate, and cannabinoid pathways, with corresponding enzyme names being similarly color-coded in the pathway schematic on the left. The numbers inside brackets indicate the numbers of DEGs. Note that the black arrow in the M-D plot illustrates the increasing gene regulation at the end of the MEP pathway. (**b**) Similar M-D plot and corresponding enzyme names in the context of the terpene biosynthetic pathways. Refer to Table S8 for corresponding gene IDs of enzymes. **Enzyme abbreviations for MEP pathway** (left to right): DXS (DOXP synthase); DXR (DXP reductio isomerase); CMS (2-C-methyl-D-erythitro1 4-phosphate cytidylltransferase); CMK (4-diphosphocytidyl-2-C-methyl-D-erythitro1 kinase); MCS (2-C-methyl-D-erythitro1 2,4-cyclodiphosphate synthase); HDS (HMB-PP synthase); HDR (HMB-PP reductase), **MVA pathway** (left to right): ACAT (acetyl-coenzyme A acetyltransferase); HMGS (HMG-CoA synthase); HMGR (HMG-CoA reductase); MK (mevalonate-5-kinase); PMK (phosphomevalonate kinase); MVD (mevalonate-5-pyrophosphate decarboxylase); IPPI (isopentenyl diphosphate isomerase); GPPS (GPP synthase), **Hexanoate pathway** (left to right): FAD (fatty acid desaturase); LOX (lipoxygenase); HPL (hydroperoxide lyase); ALDH (aldehyde dehydrogenase); AAE (acyl activating enzyme); PKS (polyketide synthase); OAC (olivetolic acid cyclase), **Cannabinoid pathway**: APT (aromatic premyl transferase); THCAS (THCA synthase); CB-DAS (CBDA synthase), **Terpene pathway** (top to bottom): MYS (myrcene synthase); LS (limonene synthase); FPPS (Farnesyl diphosphate synthase); \(\alpha\)HS (\(\alpha\)-humulee synthase); NESI (nerolidol synthase); GAS (Germancene A synthase); GGPS (geranylgeranyl diphosphate synthase). **Metabolite abbreviations in numeric and alphabetical order**: AcCoA (Acetyl co-enzyme A); AcAcCoA (Aceotoactyl CoA); ADP (adenosine diphosphate); ATP (adenosine triphosphate); CBDA (cannabidiotic acid); CBGA (cannabigerolic acid); CDP-ME (4-diphosphocytidyl-2-C-methylerythitro1); CDP-ME (4-diphosphocytidyl-2-C-methyl-D-erythitro1 2-phosphate); CoA (coenzyme A); DMAP (Dimethylallyl pyrophosphate); DXOP (deoxyxylulose 5-phosphate); FA (fatty acids); F\({}_{\text{dox}}\) (oxidized ferredoxin); Fd\({}_{\text{red}}\).