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A B C Arginine and proline PRPP Glutamine Carbamoyl-P GMP Cytosine UMP Alanine, aspartate, and glutamate Histidine Urea Cycle Pentose Phophate Pathway Purine biosynthesis Pyrimidine biosynthesis Thiamine −1 0 1 −1 0 1 −1 0 1 * * * * * * * expression correlation Environments in which genes within corems are co-regulated ec512157 ec516031 ec516034 * q-value ≤ 0.05 96 86 55 107 71 GRE 2 GRE 4 PurR ArgR MetJ IclR MetJ GRE 12 GRE 19 GRE 30 GRE 87 GRE 206 GREs nucleotide biosynthesis Ala/Asp/Glu metabolism 3.1x10 -29 6.0x10 -8 q-value amino acid biosynthesis purine biosynthesis pyrimidine biosynthesis 2.1x10 -10 2.6x10 -31 9.8x10 -93 pH diauxic shift diauxic shift carbon source carbon source amino acids q-value 9.6x10 -7 1.2x10 -6 1.7x10 -3 4.8x10 -4 1.9x10 -3 5.2x10 -11 ec516034 ec512157 ec516031 93 27 26 12 14 genes in corem shared genes D * KS-test, FDR ≤ 5% (1) GLUCOSE (2) GLYCEROL (3) ACETATE (4) SPIRAMYCIN-1 (5) CCCP-2.0 −40 −20 0 ● ● ● ● ● ● ● PurR 1 5 ● ● ● ● ● ● ● ● ***** ec516031 1 5 ● ● ● ● ● *** ec512157 1 5 ● ● ● ● ● * *** ec516034 1 5 Relative Fitness RegPrecise PurR regulon 20 22 3 Conditions (listed to right) Figure 4: Varying combinations of GREs act conditionally to subdivide and coordinate branches of the nucleotide biosynthesis pathway in an environment-dependent manner GREs implicated in co-regulating genes within corem Genes in ec516031 Genes in ec512157 Genes in ec516034 Co-regulated segment(s) of the nucleotide biosynthesis pathway Functions enriched in corem Conditions enriched in corem Figure 4. Varying combinations of GREs act conditionally to subdivide and coordinate branches of the nucleotide biosynthesis pathway in an environment- dependent manner (A) Genes of nucleotide biosynthesis are distributed in overlapping combinations across three corems: purine (ec516034 –“purine corem”), pyrimidine (ec512157–“pyrimidine corem”), or both pathways (ec516031 –“nucleotide corem”). (Left) Gene membership and overlap for the three corems as in Figure 3C. Pie charts indicate average GRE composition across all gene promoters in each corem (see Figure S3B for detail). (Top-Right Inset) GRE key for pie charts. Matches to TFs in RegulonDB noted above the GRE name. (Bottom-Right) Tables list enriched gene functions (40) and environmental conditions for each of the corems (see Supplementary Methods). (B) A portion of the nucleotide biosynthetic pathways, near the branch point dividing purine (top) and pyrimidine (bottom) biosynthesis. Pie charts represent GRE composition in each gene promoter (Key in (A)). Operons denoted by dashed lines, with only the leader gene’s promoter architecture shown. (C) Condition-specific co-expression of genes across the three corems. (Right) The active segments of nucleotide biosynthesis (as in B) are color-matched to corems. (Center) Violin plots show distributions of expression correlations between genes within each corem in relevant environmental conditions, when they are predicted to be co-regulated. Color fill and asterisks indicate corems with significantly low relative standard deviation (RSD; |σ/μ|; FDR ≤ 0.05). (Left) Colored circles indicate when genes within which corem(s) are predicted to be co-regulated (color) under how many conditions (number). (D) Distributions of relative fitness values for gene deletions in the three corems, as well as 20 of the 42 PurR regulon genes not modeled by ec516031 (black) across 5 representative conditions (condition identifiers listed to right, additional conditions in Figure S6B). Asterisks denote conditions in which the distribu- tion of fitness values is statistically significant (relative to the distribution of fitness values for all genes in that condition). See also Figure S6A-B.
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