Hypoxia response element gene transcriptions

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Associate Editor(s)-in-Chief: Henry A. Hoff

"We recently discovered a strongly conserved distal 5' [hypoxia response element] HRE and suggested that it might contribute to oxygen-regulated [Erythropoietin] EPO expression.18 This 5' HRE resides within a DNaseI hypersensitive site - 9.2 kb upstream of the EPO transcriptional start site, [WT CATACGTGCAGGGAGACACA], contains both the 5'-ACGTG-3' core [hypoxia-inducible factor] HIF DNA binding site as well as the ancillary 5'-CACA-3' element,11 and confers hypoxia-inducible exogenous reporter gene expression in Epo expressing and non-expressing cell lines.18"[1]

Human genes

Main article: Human genes

Gene expressions

Main article: Gene expressions

"We have previously shown for PAG1, another HIF-2 target gene, that a single distal - 82 kb 5' HRE resides in an isolated DNA region, bound by many additional transcription factors, and forms multiple chromatin loops both locally and over a long distance with the promoter region.21 While in this case HIF-2α did interact with the HRE, neither hypoxia nor the presence of HIF was needed for the long-range chromatin interaction with the promoter region. Only the presence of the core 5'-ACGTG-3' HIF binding DNA sequence was required to maintain this interaction, suggesting that preformed chromatin loops enable oxygen-regulated conditional gene regulation. This model has subsequently been confirmed for many other HIF target genes by genomewide approaches.38,39 Therefore, the EPO 5' HRE might well be functionally required for hypoxia-inducible gene expression by maintaining a constitutive chromatin architecture that supports promoter activity in a cell type-specific manner. The finding that only additional large but not small 5' HRE deletions fully abrogated endogenous Epo induction and HIF:promoter interaction in 3' HRE mutant Kelly cells suggests that, like in the case of the PAG1 gene, additional transcription factors bind close to the consensus HRE sequence and are involved in chromatin looping and trans-activation of the EPO promoter. We still have no explanation why a small 5' HRE deletion alone inhibited HIF-promoter interaction, but in combination with a 3' HRE mutation partially rescued the inhibitory effect of the 3' HRE mutation. Nonetheless, it is without precedent that the extended 5' HRE strongly cis-enhanced HIF binding to the promoter and 3' HRE."[1]

Interactions

Main article: Interaction gene transcriptions

Consensus sequences

Main article: Consensus sequence gene transcriptions

"Putative EPO promoter HREs. Location of two conserved potential promoter HREs (pHRE1 and pHRE2; [CACGC]) close to the GATA ([GATA]) and [Wilms tumor gene] WT1 ([GCCTCTCCCCCACCCCCACCCGCGCACGCAC]) sites in the EPO proximal 5' region. [For human and other vertebrates] is a UCSC Genome Browser output (version hg19), including 161 transcription factor ChIP-sequencing (ChIP-seq) tracks derived from the ENCODE database (version 3), clusters of DNaseI hypersensitivity sites (HSS) from 125 cell types, and the transcriptional start site (TSS), with a closer view of the region in 50 vertebrates extracted using the 100-MULTIZ whole-genome multiple sequence alignment algorithm."[1]

Binding site for

Enhancer activity

Main article: Enhancer activity copy gene transcriptions

Promoter occurrences

Main article: Promoter occurrence gene transcriptions

Hypotheses

Main article: Hypotheses
  1. A1BG has no regulatory elements in either promoter.
  2. A1BG is not transcribed by a regulatory element.
  3. No regulatory element participates in the transcription of A1BG.

Hypoxia response element samplings

Copying a responsive element consensus sequence CACGC and putting the sequence in "⌘F" finds 25 between ZNF497 and A1BG or 8 between ZSCAN22 and A1BG as can be found by the computer programs.

For the Basic programs testing consensus sequence CACGC (starting with SuccessablesHYRE.bas) written to compare nucleotide sequences with the sequences on either the template strand (-), or coding strand (+), of the DNA, in the negative direction (-), or the positive direction (+), the programs are, are looking for, and found:

  1. negative strand, negative direction, looking for CACGC, 3, CACGC at 2196, CACGC at 447, CACGC at 379.
  2. positive strand, negative direction, looking for CACGC, 5, CACGC at 3280, CACGC at 2207, CACGC at 1991, CACGC at 963, CACGC at 663.
  3. positive strand, positive direction, looking for CACGC, 14, CACGC at 1763, CACGC at 1725, CACGC at 1589, CACGC at 1521, CACGC at 1253, CACGC at 1244, CACGC at 1169, CACGC at 1160, CACGC at 1085, CACGC at 1017, CACGC at 665, CACGC at 581, CACGC at 497, CACGC at 488.
  4. negative strand, positive direction, looking for CACGC, 11, CACGC at 1553, CACGC at 1301, CACGC at 1133, CACGC at 1049, CACGC at 987, CACGC at 969, CACGC at 887, CACGC at 869, CACGC at 803, CACGC at 797, CACGC at 776.
  5. inverse complement, negative strand, negative direction, looking for GCGTG, 0.
  6. inverse complement, positive strand, negative direction, looking for GCGTG, 4, GCGTG at 3046, GCGTG at 1896, GCGTG at 1243, GCGTG at 740.
  7. inverse complement, positive strand, positive direction, looking for GCGTG, 13, GCGTG at 2565, GCGTG at 1555, GCGTG at 1551, GCGTG at 1299, GCGTG at 1135, GCGTG at 1131, GCGTG at 1051, GCGTG at 1047, GCGTG at 977, GCGTG at 877, GCGTG at 799, GCGTG at 795, GCGTG at 685.
  8. inverse complement, negative strand, positive direction, looking for GCGTG, 6, GCGTG at 2554, GCGTG at 1719, GCGTG at 1242, GCGTG at 1216, GCGTG at 1019, GCGTG at 544.

HRE (4560-2846) UTRs

  1. Positive strand, negative direction: CACGC at 3280.
  2. Positive strand, negative direction: GCGTG at 3046.

HRE negative direction (2596-1) distal promoters

  1. Negative strand, negative direction: CACGC at 2196, CACGC at 447, CACGC at 379.
  2. Positive strand, negative direction: CACGC at 2207, CACGC at 1991, CACGC at 963, CACGC at 663.
  3. Positive strand, negative direction: GCGTG at 1896, GCGTG at 1243, GCGTG at 740.

HRE positive direction (4050-1) distal promoters

  1. Negative strand, positive direction: CACGC at 1553, CACGC at 1301, CACGC at 1133, CACGC at 1049, CACGC at 987, CACGC at 969, CACGC at 887, CACGC at 869, CACGC at 803, CACGC at 797, CACGC at 776.
  2. Negative strand, positive direction: GCGTG at 2554, GCGTG at 1719, GCGTG at 1242, GCGTG at 1216, GCGTG at 1019, GCGTG at 544.
  3. Positive strand, positive direction: CACGC at 1763, CACGC at 1725, CACGC at 1589, CACGC at 1521, CACGC at 1253, CACGC at 1244, CACGC at 1169, CACGC at 1160, CACGC at 1085, CACGC at 1017, CACGC at 665, CACGC at 581, CACGC at 497, CACGC at 488.
  4. Positive strand, positive direction: GCGTG at 2565, GCGTG at 1555, GCGTG at 1551, GCGTG at 1299, GCGTG at 1135, GCGTG at 1131, GCGTG at 1051, GCGTG at 1047, GCGTG at 977, GCGTG at 877, GCGTG at 799, GCGTG at 795, GCGTG at 685.

HRE random dataset samplings

  1. HREr0: 2, CACGC at 3732, CACGC at 661.
  2. HREr1: 1, CACGC at 2663.
  3. HREr2: 4, CACGC at 2926, CACGC at 2252, CACGC at 1929, CACGC at 1467.
  4. HREr3: 4, CACGC at 1818, CACGC at 586, CACGC at 176, CACGC at 142.
  5. HREr4: 0.
  6. HREr5: 8, CACGC at 4134, CACGC at 3471, CACGC at 2699, CACGC at 2676, CACGC at 1788, CACGC at 1099, CACGC at 77, CACGC at 73.
  7. HREr6: 2, CACGC at 2172, CACGC at 1673.
  8. HREr7: 0.
  9. HREr8: 2, CACGC at 1084, CACGC at 14.
  10. HREr9: 4, CACGC at 3738, CACGC at 3436, CACGC at 2116, CACGC at 1360.
  11. HREr0ci: 4, GCGTG at 3280, GCGTG at 3076, GCGTG at 1379, GCGTG at 1076.
  12. HREr1ci: 1, GCGTG at 695.
  13. RHREr2ci: 4, GCGTG at 3087, GCGTG at 2458, GCGTG at 1241, GCGTG at 591.
  14. HREr3ci: 1, GCGTG at 1530.
  15. HREr4ci: 3, GCGTG at 3732, GCGTG at 1562, GCGTG at 957.
  16. HREr5ci: 5, GCGTG at 4373, GCGTG at 4314, GCGTG at 3955, GCGTG at 2404, GCGTG at 370.
  17. HREr6ci: 2, GCGTG at 1335, GCGTG at 658.
  18. HREr7ci: 6, GCGTG at 3561, GCGTG at 3315, GCGTG at 2296, GCGTG at 1789, GCGTG at 452, GCGTG at 336.
  19. HREr8ci: 3, GCGTG at 4128, GCGTG at 2273, GCGTG at 303.
  20. HREr9ci: 2, GCGTG at 1430, GCGTG at 428.

HREr arbitrary (evens) (4560-2846) UTRs

  1. HREr0: CACGC at 3732.
  2. HREr2: CACGC at 2926.
  3. HREr0ci: GCGTG at 3280, GCGTG at 3076.
  4. HREr2ci: GCGTG at 3087.
  5. HREr4ci: GCGTG at 3732.
  6. HREr8ci: GCGTG at 4128.

HREr alternate (odds) (4560-2846) UTRs

  1. HREr5: CACGC at 4134, CACGC at 3471.
  2. HREr9: CACGC at 3738, CACGC at 3436.
  3. HREr5ci: GCGTG at 4373, GCGTG at 4314, GCGTG at 3955.
  4. HREr7ci: GCGTG at 3561, GCGTG at 3315.

HREr arbitrary positive direction (odds) (4445-4265) core promoters

  1. HREr5ci: GCGTG at 4373, GCGTG at 4314.

HREr alternate negative direction (odds) (2811-2596) proximal promoters

  1. HREr1: CACGC at 2663.
  2. HREr5: CACGC at 2699, CACGC at 2676.

HREr arbitrary positive direction (odds) (4265-4050) proximal promoters

  1. HREr5: CACGC at 4134.

HREr alternate positive direction (evens) (4265-4050) proximal promoters

  1. HREr8ci: GCGTG at 4128.

HREr arbitrary negative direction (evens) (2596-1) distal promoters

  1. HREr0: CACGC at 661.
  2. HREr2: CACGC at 2252, CACGC at 1929, CACGC at 1467.
  3. HREr6: CACGC at 2172, CACGC at 1673.
  4. HREr8: CACGC at 1084, CACGC at 14.
  5. HREr0ci: GCGTG at 1379, GCGTG at 1076.
  6. HREr2ci: GCGTG at 2458, GCGTG at 1241, GCGTG at 591.
  7. HREr4ci: GCGTG at 1562, GCGTG at 957.
  8. HREr6ci: GCGTG at 1335, GCGTG at 658.
  9. HREr8ci: GCGTG at 2273, GCGTG at 303.

HREr alternate negative direction (odds) (2596-1) distal promoters

  1. HREr3: CACGC at 1818, CACGC at 586, CACGC at 176, CACGC at 142.
  2. HREr5: CACGC at 1788, CACGC at 1099, CACGC at 77, CACGC at 73.
  3. HREr9: CACGC at 2116, CACGC at 1360.
  4. HREr1ci: GCGTG at 695.
  5. HREr3ci: GCGTG at 1530.
  6. HREr5ci: GCGTG at 2404, GCGTG at 370.
  7. HREr7ci: GCGTG at 2296, GCGTG at 1789, GCGTG at 452, GCGTG at 336.
  8. HREr9ci: GCGTG at 1430, GCGTG at 428.

HREr arbitrary positive direction (odds) (4050-1) distal promoters

  1. HREr1: CACGC at 2663.
  2. HREr3: CACGC at 1818, CACGC at 586, CACGC at 176, CACGC at 142.
  3. HREr5: CACGC at 3471, CACGC at 2699, CACGC at 2676, CACGC at 1788, CACGC at 1099, CACGC at 77, CACGC at 73.
  4. HREr9: CACGC at 3738, CACGC at 3436, CACGC at 2116, CACGC at 1360.
  5. HREr1ci: GCGTG at 695.
  6. HREr3ci: GCGTG at 1530.
  7. HREr5ci: GCGTG at 3955, GCGTG at 2404, GCGTG at 370.
  8. HREr7ci: GCGTG at 3561, GCGTG at 3315, GCGTG at 2296, GCGTG at 1789, GCGTG at 452, GCGTG at 336.
  9. HREr9ci: GCGTG at 1430, GCGTG at 428.

HREr alternate positive direction (evens) (4050-1) distal promoters

  1. HREr0: CACGC at 3732, CACGC at 661.
  2. HREr2: CACGC at 2926, CACGC at 2252, CACGC at 1929, CACGC at 1467.
  3. HREr6: CACGC at 2172, CACGC at 1673.
  4. HREr8: CACGC at 1084, CACGC at 14.
  5. HREr0ci: GCGTG at 3280, GCGTG at 3076, GCGTG at 1379, GCGTG at 1076.
  6. RHREr2ci: GCGTG at 3087, GCGTG at 2458, GCGTG at 1241, GCGTG at 591.
  7. HREr4ci: GCGTG at 3732, GCGTG at 1562, GCGTG at 957.
  8. HREr6ci: GCGTG at 1335, GCGTG at 658.
  9. HREr8ci: GCGTG at 2273, GCGTG at 303.

Hypoxia response element analysis and results

Main article: Complex locus A1BG and ZNF497 § HREs

"Putative EPO promoter HREs. Location of two conserved potential promoter HREs (pHRE1 and pHRE2; [CACGC]) close to the GATA ([GATA]) and [Wilms tumor gene] WT1 ([GCCTCTCCCCCACCCCCACCCGCGCACGCAC]) sites in the EPO proximal 5' region."[1]

Reals or randoms Promoters direction Numbers Strands Occurrences Averages (± 0.1)
Reals UTR negative 2 2 1 1 ± 1 (--0,+-2)
Randoms UTR arbitrary negative 7 10 0.7 0.8
Randoms UTR alternate negative 9 10 0.9 0.8
Reals Core negative 0 2 0 0
Randoms Core arbitrary negative 0 10 0 0
Randoms Core alternate negative 0 10 0 0
Reals Core positive 0 2 0 0
Randoms Core arbitrary positive 2 10 0.2 0.1
Randoms Core alternate positive 0 10 0 0.1
Reals Proximal negative 0 2 0 0
Randoms Proximal arbitrary negative 0 10 0 0.15
Randoms Proximal alternate negative 3 10 0.3 0.15
Reals Proximal positive 0 2 0 0
Randoms Proximal arbitrary positive 1 10 0.1 0.1
Randoms Proximal alternate positive 1 10 0.1 0.1
Reals Distal negative 10 2 5 5 ± 2 (--3,+-7)
Randoms Distal arbitrary negative 19 10 1.9 1.95
Randoms Distal alternate negative 20 10 2.0 1.95
Reals Distal positive 44 2 22 22 ± 5 (-+17,++27)
Randoms Distal arbitrary positive 29 10 2.9 2.7
Randoms Distal alternate positive 25 10 2.5 2.7

Comparison:

The occurrences of real hypoxia response elements are greater than the randoms. This suggests that the real hypoxia response elements are likely active or activable.

CACA samplings

Copying a responsive elements consensus sequence CACA and putting the sequence in "⌘F" finds 30 between ZNF497 and A1BG or 13 between ZSCAN22 and A1BG as can be found by the computer programs.

For the Basic programs testing consensus sequence CACA (starting with SuccessablesCACA.bas) written to compare nucleotide sequences with the sequences on either the template strand (-), or coding strand (+), of the DNA, in the negative direction (-), or the positive direction (+), the programs are, are looking for, and found:

  1. Negative strand, negative direction: 15, CACA at 4359, CACA at 3939, CACA at 3558, CACA at 3184, CACA at 2860, CACA at 2656, CACA at 2603, CACA at 2085, CACA at 1477, CACA at 1220, CACA at 795, CACA at 793, CACA at 610, CACA at 608, CACA at 322.
  2. Positive strand, negative direction: 24, CACA at 4531, CACA at 4196, CACA at 3965, CACA at 3915, CACA at 3764, CACA at 3692, CACA at 3670, CACA at 3632, CACA at 3513, CACA at 3391, CACA at 2687, CACA at 2665, CACA at 2416, CACA at 2242, CACA at 1719, CACA at 1541, CACA at 1126, CACA at 1116, CACA at 960, CACA at 880, CACA at 528, CACA at 518, CACA at 295, CACA at 266.
  3. Negative strand, positive direction, looking for CACA, 34, CACA at 3954, CACA at 3859, CACA at 3822, CACA at 3740, CACA at 3705, CACA at 3505, CACA at 3411, CACA at 3409, CACA at 3209, CACA at 3192, CACA at 3098, CACA at 3096, CACA at 2962, CACA at 2835, CACA at 2634, CACA at 2600, CACA at 2123, CACA at 2029, CACA at 1822, CACA at 1695, CACA at 1556, CACA at 1220, CACA at 1136, CACA at 1052, CACA at 984, CACA at 884, CACA at 800, CACA at 716, CACA at 714, CACA at 632, CACA at 550, CACA at 548, CACA at 343, CACA at 155.
  4. Positive strand, positive direction: 15, CACA at 3969, CACA at 3964, CACA at 3950, CACA at 3592, CACA at 2813, CACA at 2464, CACA at 2252, CACA at 2170, CACA at 2076, CACA at 1969, CACA at 1803, CACA at 1020, CACA at 266, CACA at 105, CACA at 80.
  5. inverse complement, negative strand, negative direction: 20, TGTG at 4469, TGTG at 4334, TGTG at 4195, TGTG at 3981, TGTG at 3966, TGTG at 3669, TGTG at 3512, TGTG at 3390, TGTG at 2686, TGTG at 2549, TGTG at 2417, TGTG at 1542, TGTG at 1540, TGTG at 1127, TGTG at 961, TGTG at 881, TGTG at 747, TGTG at 529, TGTG at 340, TGTG at 60.
  6. inverse complement, positive strand, negative direction:, 19, TGTG at 4400, TGTG at 4360, TGTG at 4091, TGTG at 3958, TGTG at 3809, TGTG at 3710, TGTG at 3559, TGTG at 3557, TGTG at 3427, TGTG at 3266, TGTG at 3185, TGTG at 2861, TGTG at 2657, TGTG at 2604, TGTG at 2064, TGTG at 1478, TGTG at 794, TGTG at 786, TGTG at 609.
  7. inverse complement, negative strand, positive direction: 19, TGTG at 4393, TGTG at 3970, TGTG at 3965, TGTG at 3958, TGTG at 3902, TGTG at 3641, TGTG at 3593, TGTG at 3435, TGTG at 2958, TGTG at 2679, TGTG at 2251, TGTG at 2075, TGTG at 1970, TGTG at 1804, TGTG at 1021, TGTG at 917, TGTG at 817, TGTG at 265, TGTG at 229.
  8. inverse complement, positive strand, positive direction: 26, TGTG at 4333, TGTG at 4257, TGTG at 3823, TGTG at 3531, TGTG at 3506, TGTG at 3410, TGTG at 3097, TGTG at 3095, TGTG at 2963, TGTG at 2834, TGTG at 2635, TGTG at 2601, TGTG at 2429, TGTG at 1696, TGTG at 1694, TGTG at 1557, TGTG at 1221, TGTG at 1137, TGTG at 985, TGTG at 885, TGTG at 801, TGTG at 715, TGTG at 713, TGTG at 567, TGTG at 549, TGTG at 344.

CACA UTRs

  1. Negative strand, negative direction: TGTG at 4469, CACA at 4359, TGTG at 4334, TGTG at 4195, TGTG at 3981, TGTG at 3966, CACA at 3939, TGTG at 3669, CACA at 3558, TGTG at 3512, TGTG at 3390, CACA at 3184, CACA at 2860.
  2. Positive strand, negative direction: CACA at 4531, TGTG at 4400, TGTG at 4360, CACA at 4196, TGTG at 4091, CACA at 3965, TGTG at 3958, CACA at 3915, TGTG at 3809, CACA at 3764, TGTG at 3710, CACA at 3692, CACA at 3670, CACA at 3632, TGTG at 3559, TGTG at 3557, CACA at 3513, TGTG at 3427, CACA at 3391, TGTG at 3266, TGTG at 3185, TGTG at 2861.

CACA positive direction core promoters

  1. Negative strand, positive direction: TGTG at 4393.
  2. Positive strand, positive direction: TGTG at 4333.

CACA negative direction proximal promoters

  1. Negative strand, negative direction: TGTG at 2686, CACA at 2656, CACA at 2603.
  2. Positive strand, negative direction: CACA at 2687, CACA at 2665, TGTG at 2657, TGTG at 2604.

CACA positive direction proximal promoters

  1. Positive strand, positive direction: TGTG at 4257.

CACA negative direction distal promoters

  1. Negative strand, negative direction: TGTG at 2549, TGTG at 2417, CACA at 2085, TGTG at 1542, TGTG at 1540, CACA at 1477, CACA at 1220, TGTG at 1127, TGTG at 961, TGTG at 881, CACA at 795, CACA at 793, TGTG at 747, CACA at 610, CACA at 608, TGTG at 529, TGTG at 340, CACA at 322, TGTG at 60.
  2. Positive strand, negative direction: CACA at 2416, CACA at 2242, TGTG at 2064, CACA at 1719, CACA at 1541, TGTG at 1478, CACA at 1126, CACA at 1116, CACA at 960, CACA at 880, TGTG at 794, TGTG at 786, TGTG at 609, CACA at 528, CACA at 518, CACA at 295, CACA at 266.

CACA positive direction distal promoters

  1. Negative strand, positive direction: TGTG at 3970, TGTG at 3965, TGTG at 3958, CACA at 3954, TGTG at 3902, CACA at 3859, CACA at 3822, CACA at 3740, CACA at 3705, TGTG at 3641, TGTG at 3593, CACA at 3505, TGTG at 3435, CACA at 3411, CACA at 3409, CACA at 3209, CACA at 3192, CACA at 3098, CACA at 3096, CACA at 2962, TGTG at 2958, CACA at 2835, TGTG at 2679, CACA at 2634, CACA at 2600, TGTG at 2251, CACA at 2123, TGTG at 2075, CACA at 2029, TGTG at 1970, CACA at 1822, TGTG at 1804, CACA at 1695, CACA at 1556, CACA at 1220, CACA at 1136, CACA at 1052, TGTG at 1021, CACA at 984, TGTG at 917, CACA at 884, TGTG at 817, CACA at 800, CACA at 716, CACA at 714, CACA at 632, CACA at 550, CACA at 548, CACA at 343, TGTG at 265, TGTG at 229, CACA at 155.
  2. Positive strand, positive direction: CACA at 3969, CACA at 3964, CACA at 3950, TGTG at 3823, CACA at 3592, TGTG at 3531, TGTG at 3506, TGTG at 3410, TGTG at 3097, TGTG at 3095, TGTG at 2963, TGTG at 2834, CACA at 2813, TGTG at 2635, TGTG at 2601, CACA at 2464, TGTG at 2429, CACA at 2252, CACA at 2170, CACA at 2076, CACA at 1969, CACA at 1803, TGTG at 1696, TGTG at 1694, TGTG at 1557, TGTG at 1221, TGTG at 1137, CACA at 1020, TGTG at 985, TGTG at 885, TGTG at 801, TGTG at 715, TGTG at 713, TGTG at 567, TGTG at 549, TGTG at 344, CACA at 266, CACA at 105, CACA at 80.

CACA element random dataset samplings

  1. CACAr0: 12, CACA at 4434, CACA at 3574, CACA at 3394, CACA at 3071, CACA at 2453, CACA at 2451, CACA at 2207, CACA at 2162, CACA at 1785, CACA at 1606, CACA at 1163, CACA at 887.
  2. CACAr1: 10, CACA at 4523, CACA at 4235, CACA at 4138, CACA at 3172, CACA at 2696, CACA at 2259, CACA at 985, CACA at 742, CACA at 442, CACA at 178.
  3. CACAr2: 19, CACA at 4319, CACA at 4088, CACA at 4066, CACA at 3836, CACA at 3732, CACA at 2829, CACA at 2807, CACA at 2805, CACA at 2803, CACA at 2682, CACA at 2421, CACA at 2220, CACA at 2026, CACA at 1797, CACA at 1306, CACA at 1087, CACA at 509, CACA at 59, CACA at 57.
  4. CACAr3: 6, CACA at 4283, CACA at 2737, CACA at 2701, CACA at 2699, CACA at 2697, CACA at 434.
  5. CACAr4: 10, CACA at 4394, CACA at 4362, CACA at 4198, CACA at 2197, CACA at 1968, CACA at 1773, CACA at 1771, CACA at 1253, CACA at 907, CACA at 236.
  6. CACAr5: 9, CACA at 4072, CACA at 3432, CACA at 3430, CACA at 3416, CACA at 3343, CACA at 1640, CACA at 1479, CACA at 1282, CACA at 389.
  7. CACAr6: 17, CACA at 4391, CACA at 4196, CACA at 3770, CACA at 3628, CACA at 3161, CACA at 3074, CACA at 2599, CACA at 2355, CACA at 2312, CACA at 1941, CACA at 1838, CACA at 1776, CACA at 1670, CACA at 1297, CACA at 1166, CACA at 967, CACA at 580.
  8. CACAr7: 8, CACA at 3896, CACA at 3641, CACA at 3266, CACA at 2680, CACA at 1204, CACA at 814, CACA at 378, CACA at 198.
  9. CACAr8: 10, CACA at 4336, CACA at 3962, CACA at 3711, CACA at 1946, CACA at 1903, CACA at 1753, CACA at 1751, CACA at 1503, CACA at 1049, CACA at 658.
  10. CACAr9: 17, CACA at 4069, CACA at 4050, CACA at 4031, CACA at 3735, CACA at 3451, CACA at 3449, CACA at 3080, CACA at 2711, CACA at 2021, CACA at 1814, CACA at 1674, CACA at 1520, CACA at 1096, CACA at 415, CACA at 304, CACA at 302, CACA at 60.
  11. CACAr0ci: 17, TGTG at 4534, TGTG at 4106, TGTG at 3956, TGTG at 3931, TGTG at 3768, TGTG at 3669, TGTG at 3019, TGTG at 2842, TGTG at 2063, TGTG at 1942, TGTG at 1940, TGTG at 1825, TGTG at 1758, TGTG at 1059, TGTG at 764, TGTG at 724, TGTG at 461.
  12. CACAr1ci: 18, TGTG at 3974, TGTG at 3891, TGTG at 3401, TGTG at 2904, TGTG at 2754, TGTG at 2528, TGTG at 2390, TGTG at 2025, TGTG at 1803, TGTG at 1583, TGTG at 1581, TGTG at 871, TGTG at 697, TGTG at 640, TGTG at 534, TGTG at 347, TGTG at 282, TGTG at 44.
  13. CACAr2ci: 13, TGTG at 4487, TGTG at 3894, TGTG at 3505, TGTG at 2764, TGTG at 2546, TGTG at 2200, TGTG at 1999, TGTG at 1052, TGTG at 726, TGTG at 702, TGTG at 527, TGTG at 458, TGTG at 166.
  14. CACAr3ci: 15, TGTG at 4318, TGTG at 3853, TGTG at 3771, TGTG at 3437, TGTG at 2968, TGTG at 2669, TGTG at 2446, TGTG at 2205, TGTG at 2010, TGTG at 1573, TGTG at 1134, TGTG at 1106, TGTG at 640, TGTG at 511, TGTG at 93.
  15. CACAr4ci: 16, TGTG at 4072, TGTG at 4054, TGTG at 4035, TGTG at 3604, TGTG at 3539, TGTG at 3250, TGTG at 2981, TGTG at 2760, TGTG at 2243, TGTG at 2224, TGTG at 1960, TGTG at 1823, TGTG at 1455, TGTG at 1356, TGTG at 1316, TGTG at 286.
  16. CACAr5ci: 15, TGTG at 4498, TGTG at 4041, TGTG at 3880, TGTG at 3551, TGTG at 3373, TGTG at 2854, TGTG at 2836, TGTG at 2670, TGTG at 2053, TGTG at 1899, TGTG at 1721, TGTG at 1696, TGTG at 1547, TGTG at 1129, TGTG at 322.
  17. CACAr6ci: 11, TGTG at 4475, TGTG at 4364, TGTG at 3044, TGTG at 2947, TGTG at 2653, TGTG at 2421, TGTG at 2330, TGTG at 2004, TGTG at 1745, TGTG at 1342, TGTG at 100.
  18. CACAr7ci: 14, TGTG at 4508, TGTG at 4226, TGTG at 2153, TGTG at 2139, TGTG at 1679, TGTG at 1509, TGTG at 1402, TGTG at 1353, TGTG at 1327, TGTG at 1311, TGTG at 917, TGTG at 493, TGTG at 338, TGTG at 118.
  19. CACAr8ci: 10, TGTG at 4236, TGTG at 4234, TGTG at 2728, TGTG at 1713, TGTG at 1284, TGTG at 1172, TGTG at 536, TGTG at 523, TGTG at 451, TGTG at 439.
  20. CACAr9ci: 5, TGTG at 4389, TGTG at 2254, TGTG at 1975, TGTG at 1469, TGTG at 470.

CACAr arbitrary UTRs

  1. CACAr0: CACA at 4434, CACA at 3574, CACA at 3394, CACA at 3071.
  2. CACAr2: CACA at 4319, CACA at 4088, CACA at 4066, CACA at 3836, CACA at 3732.
  3. CACAr4: CACA at 4394, CACA at 4362, CACA at 4198.
  4. CACAr6: CACA at 4391, CACA at 4196, CACA at 3770, CACA at 3628, CACA at 3161, CACA at 3074.
  5. CACAr8: CACA at 4336, CACA at 3962, CACA at 3711.
  6. CACAr0ci: TGTG at 4534, TGTG at 4106, TGTG at 3956, TGTG at 3931, TGTG at 3768, TGTG at 3669, TGTG at 3019.
  7. CACAr2ci: TGTG at 4487, TGTG at 3894, TGTG at 3505.
  8. CACAr4ci: TGTG at 4072, TGTG at 4054, TGTG at 4035, TGTG at 3604, TGTG at 3539, TGTG at 3250, TGTG at 2981.
  9. CACAr6ci: TGTG at 4475, TGTG at 4364, TGTG at 3044, TGTG at 2947.
  10. CACAr8ci: TGTG at 4236, TGTG at 4234.

CACAr alternate UTRs

  1. CACAr1: CACA at 4523, CACA at 4235, CACA at 4138, CACA at 3172.
  2. CACAr3: CACA at 4283.
  3. CACAr5: CACA at 4072, CACA at 3432, CACA at 3430, CACA at 3416, CACA at 3343.
  4. CACAr7: CACA at 3896, CACA at 3641, CACA at 3266.
  5. CACAr9: CACA at 4069, CACA at 4050, CACA at 4031, CACA at 3735, CACA at 3451, CACA at 3449, CACA at 3080.
  6. CACAr1ci: TGTG at 3974, TGTG at 3891, TGTG at 3401, TGTG at 2904.
  7. CACAr3ci: TGTG at 4318, TGTG at 3853, TGTG at 3771, TGTG at 3437, TGTG at 2968.
  8. CACAr5ci: TGTG at 4498, TGTG at 4041, TGTG at 3880, TGTG at 3551, TGTG at 3373, TGTG at 2854.
  9. CACAr7ci: TGTG at 4508, TGTG at 4226.
  10. CACAr9ci: TGTG at 4389.

CACAr arbitrary negative direction core promoters

  1. CACAr2: CACA at 2829.
  2. CACAr0ci: TGTG at 2842.

CACAr alternate negative direction core promoters

  1. CACAr5ci: TGTG at 2836.

CACAr arbitrary positive direction core promoters

  1. CACAr3: CACA at 4283.
  2. CACAr3ci: TGTG at 4318.
  3. CACAr9ci: TGTG at 4389.

CACAr alternate positive direction core promoters

  1. CACAr0: CACA at 4434.
  2. CACAr2: CACA at 4319.
  3. CACAr4: CACA at 4394, CACA at 4362.
  4. CACAr6: CACA at 4391.
  5. CACAr6ci: TGTG at 4364.

CACAr arbitrary negative direction proximal promoters

  1. CACAr2: CACA at 2807, CACA at 2805, CACA at 2803, CACA at 2682.
  2. CACAr6: CACA at 2599.
  3. CACAr2ci: TGTG at 2764.
  4. CACAr4ci: TGTG at 2760.
  5. CACAr6ci: TGTG at 2653.
  6. CACAr8ci: TGTG at 2728.

CACAr alternate negative direction proximal promoters

  1. CACAr1: CACA at 2696.
  2. CACAr3: CACA at 2737, CACA at 2701, CACA at 2699, CACA at 2697.
  3. CACAr9: CACA at 2711.
  4. CACAr1ci: TGTG at 2754.
  5. CACAr3ci: TGTG at 2669.
  6. CACAr5ci: TGTG at 2670.

CACAr arbitrary positive direction proximal promoters

  1. CACAr1: CACA at 4235, CACA at 4138.
  2. CACAr5: CACA at 4072.
  3. CACAr9: CACA at 4069, CACA at 4050.
  4. CACAr7ci: TGTG at 4226.

CACAr alternate positive direction proximal promoters

  1. CACAr2: CACA at 4088, CACA at 4066.
  2. CACAr4: CACA at 4198.
  3. CACAr6: CACA at 4196.
  4. CACAr0ci: TGTG at 4106.
  5. CACAr4ci: TGTG at 4072, TGTG at 4054.
  6. CACAr8ci: TGTG at 4236, TGTG at 4234.

CACAr arbitrary negative direction distal promoters

  1. CACAr0: CACA at 2453, CACA at 2451, CACA at 2207, CACA at 2162, CACA at 1785, CACA at 1606, CACA at 1163, CACA at 887.
  2. CACAr2: CACA at 2421, CACA at 2220, CACA at 2026, CACA at 1797, CACA at 1306, CACA at 1087, CACA at 509, CACA at 59, CACA at 57.
  3. CACAr4: CACA at 2197, CACA at 1968, CACA at 1773, CACA at 1771, CACA at 1253, CACA at 907, CACA at 236.
  4. CACAr6: CACA at 2599, CACA at 2355, CACA at 2312, CACA at 1941, CACA at 1838, CACA at 1776, CACA at 1670, CACA at 1297, CACA at 1166, CACA at 967, CACA at 580.
  5. CACAr8: CACA at 1946, CACA at 1903, CACA at 1753, CACA at 1751, CACA at 1503, CACA at 1049, CACA at 658.
  6. CACAr0ci: TGTG at 2063, TGTG at 1942, TGTG at 1940, TGTG at 1825, TGTG at 1758, TGTG at 1059, TGTG at 764, TGTG at 724, TGTG at 461.
  7. CACAr2ci: TGTG at 2546, TGTG at 2200, TGTG at 1999, TGTG at 1052, TGTG at 726, TGTG at 702, TGTG at 527, TGTG at 458, TGTG at 166.
  8. CACAr4ci: TGTG at 4035, TGTG at 3604, TGTG at 3539, TGTG at 3250, TGTG at 2981, TGTG at 2760, TGTG at 2243, TGTG at 2224, TGTG at 1960, TGTG at 1823, TGTG at 1455, TGTG at 1356, TGTG at 1316, TGTG at 286.
  9. CACAr6ci: TGTG at 3044, TGTG at 2947, TGTG at 2653, TGTG at 2421, TGTG at 2330, TGTG at 2004, TGTG at 1745, TGTG at 1342, TGTG at 100.
  10. CACAr8ci: TGTG at 1713, TGTG at 1284, TGTG at 1172, TGTG at 536, TGTG at 523, TGTG at 451, TGTG at 439.

CACAr alternate negative direction distal promoters

  1. CACAr1: CACA at 2259, CACA at 985, CACA at 742, CACA at 442, CACA at 178.
  2. CACAr3: CACA at 434.
  3. CACAr5: CACA at 1640, CACA at 1479, CACA at 1282, CACA at 389.
  4. CACAr7: CACA at 1204, CACA at 814, CACA at 378, CACA at 198.
  5. CACAr9: CACA at 2021, CACA at 1814, CACA at 1674, CACA at 1520, CACA at 1096, CACA at 415, CACA at 304, CACA at 302, CACA at 60.
  6. CACAr1ci: TGTG at 2528, TGTG at 2390, TGTG at 2025, TGTG at 1803, TGTG at 1583, TGTG at 1581, TGTG at 871, TGTG at 697, TGTG at 640, TGTG at 534, TGTG at 347, TGTG at 282, TGTG at 44.
  7. CACAr3ci: TGTG at 2446, TGTG at 2205, TGTG at 2010, TGTG at 1573, TGTG at 1134, TGTG at 1106, TGTG at 640, TGTG at 511, TGTG at 93.
  8. CACAr5ci: TGTG at 2053, TGTG at 1899, TGTG at 1721, TGTG at 1696, TGTG at 1547, TGTG at 1129, TGTG at 322.
  9. CACAr7ci: TGTG at 2153, TGTG at 2139, TGTG at 1679, TGTG at 1509, TGTG at 1402, TGTG at 1353, TGTG at 1327, TGTG at 1311, TGTG at 917, TGTG at 493, TGTG at 338, TGTG at 118.
  10. CACAr9ci: TGTG at 2254, TGTG at 1975, TGTG at 1469, TGTG at 470.

CACAr arbitrary positive direction distal promoters

  1. CACAr1: CACA at 3172, CACA at 2696, CACA at 2259, CACA at 985, CACA at 742, CACA at 442, CACA at 178.
  2. CACAr3: CACA at 2737, CACA at 2701, CACA at 2699, CACA at 2697, CACA at 434.
  3. CACAr5: CACA at 3432, CACA at 3430, CACA at 3416, CACA at 3343, CACA at 1640, CACA at 1479, CACA at 1282, CACA at 389.
  4. CACAr7: CACA at 3896, CACA at 3641, CACA at 3266, CACA at 2680, CACA at 1204, CACA at 814, CACA at 378, CACA at 198.
  5. CACAr9: CACA at 4050, CACA at 4031, CACA at 3735, CACA at 3451, CACA at 3449, CACA at 3080, CACA at 2711, CACA at 2021, CACA at 1814, CACA at 1674, CACA at 1520, CACA at 1096, CACA at 415, CACA at 304, CACA at 302, CACA at 60.
  6. CACAr1ci: TGTG at 3974, TGTG at 3891, TGTG at 3401, TGTG at 2904, TGTG at 2754, TGTG at 2528, TGTG at 2390, TGTG at 2025, TGTG at 1803, TGTG at 1583, TGTG at 1581, TGTG at 871, TGTG at 697, TGTG at 640, TGTG at 534, TGTG at 347, TGTG at 282, TGTG at 44.
  7. CACAr3ci: TGTG at 3853, TGTG at 3771, TGTG at 3437, TGTG at 2968, TGTG at 2669, TGTG at 2446, TGTG at 2205, TGTG at 2010, TGTG at 1573, TGTG at 1134, TGTG at 1106, TGTG at 640, TGTG at 511, TGTG at 93.
  8. CACAr5ci: TGTG at 4041, TGTG at 3880, TGTG at 3551, TGTG at 3373, TGTG at 2854, TGTG at 2836, TGTG at 2670, TGTG at 2053, TGTG at 1899, TGTG at 1721, TGTG at 1696, TGTG at 1547, TGTG at 1129, TGTG at 322.
  9. CACAr7ci: TGTG at 2153, TGTG at 2139, TGTG at 1679, TGTG at 1509, TGTG at 1402, TGTG at 1353, TGTG at 1327, TGTG at 1311, TGTG at 917, TGTG at 493, TGTG at 338, TGTG at 118.
  10. CACAr9ci: TGTG at 2254, TGTG at 1975, TGTG at 1469, TGTG at 470.

CACAr alternate positive direction distal promoters

  1. CACAr0: CACA at 3574, CACA at 3394, CACA at 3071, CACA at 2453, CACA at 2451, CACA at 2207, CACA at 2162, CACA at 1785, CACA at 1606, CACA at 1163, CACA at 887.
  2. CACAr2: CACA at 3836, CACA at 3732, CACA at 2829, CACA at 2807, CACA at 2805, CACA at 2803, CACA at 2682, CACA at 2421, CACA at 2220, CACA at 2026, CACA at 1797, CACA at 1306, CACA at 1087, CACA at 509, CACA at 59, CACA at 57.
  3. CACAr4: CACA at 2197, CACA at 1968, CACA at 1773, CACA at 1771, CACA at 1253, CACA at 907, CACA at 236.
  4. CACAr6: CACA at 3770, CACA at 3628, CACA at 3161, CACA at 3074, CACA at 2599, CACA at 2355, CACA at 2312, CACA at 1941, CACA at 1838, CACA at 1776, CACA at 1670, CACA at 1297, CACA at 1166, CACA at 967, CACA at 580.
  5. CACAr8: CACA at 3962, CACA at 3711, CACA at 1946, CACA at 1903, CACA at 1753, CACA at 1751, CACA at 1503, CACA at 1049, CACA at 658.
  6. CACAr0ci: TGTG at 3956, TGTG at 3931, TGTG at 3768, TGTG at 3669, TGTG at 3019, TGTG at 2842, TGTG at 2063, TGTG at 1942, TGTG at 1940, TGTG at 1825, TGTG at 1758, TGTG at 1059, TGTG at 764, TGTG at 724, TGTG at 461.
  7. CACAr2ci: TGTG at 3894, TGTG at 3505, TGTG at 2764, TGTG at 2546, TGTG at 2200, TGTG at 1999, TGTG at 1052, TGTG at 726, TGTG at 702, TGTG at 527, TGTG at 458, TGTG at 166.
  8. CACAr4ci: TGTG at 4035, TGTG at 3604, TGTG at 3539, TGTG at 3250, TGTG at 2981, TGTG at 2760, TGTG at 2243, TGTG at 2224, TGTG at 1960, TGTG at 1823, TGTG at 1455, TGTG at 1356, TGTG at 1316, TGTG at 286.
  9. CACAr6ci: TGTG at 3044, TGTG at 2947, TGTG at 2653, TGTG at 2421, TGTG at 2330, TGTG at 2004, TGTG at 1745, TGTG at 1342, TGTG at 100.
  10. CACAr8ci: TGTG at 2728, TGTG at 1713, TGTG at 1284, TGTG at 1172, TGTG at 536, TGTG at 523, TGTG at 451, TGTG at 439.

CACA element analysis and results

Main article: Complex locus A1BG and ZNF497 § CACAs

"This 5' HRE resides within a DNaseI hypersensitive site - 9.2 kb upstream of the EPO transcriptional start site, [WT CATACGTGCAGGGAGACACA], contains both the 5'-ACGTG-3' core [hypoxia-inducible factor] HIF DNA binding site as well as the ancillary 5'-CACA-3' element,11 and confers hypoxia-inducible exogenous reporter gene expression in Epo expressing and non-expressing cell lines.18"[1]

Reals or randoms Promoters direction Numbers Strands Occurrences Averages (± 0.1)
Reals UTR negative 35 2 17.5 17.5 (--13,+-22)
Randoms UTR arbitrary negative 44 10 4.4 4.1
Randoms UTR alternate negative 38 10 3.8 4.1
Reals Core negative 0 2 0 0
Randoms Core arbitrary negative 2 10 0.2 0.15
Randoms Core alternate negative 1 10 0.1 0.15
Reals Core positive 2 2 1 1
Randoms Core arbitrary positive 3 10 0.3 0.45
Randoms Core alternate positive 6 10 0.6 0.45
Reals Proximal negative 7 2 3.5 3.5 (--3,+-4)
Randoms Proximal arbitrary negative 9 10 0.9 0.9
Randoms Proximal alternate negative 9 10 0.9 0.9
Reals Proximal positive 1 2 0.5 0.5 (-+0,++1)
Randoms Proximal arbitrary positive 6 10 0.6 0.75
Randoms Proximal alternate positive 9 10 0.9 0.75
Reals Distal negative 36 2 18 18 (--19,+-17)
Randoms Distal arbitrary negative 90 10 9 7.9
Randoms Distal alternate negative 68 10 6.8 7.9
Reals Distal positive 91 2 45.5 45.5(-+52,++39)
Randoms Distal arbitrary positive 106 10 10.6 11.1
Randoms Distal alternate positive 116 10 11.6 11.1

Comparison:

The occurrences of real CACA elements: UTRs, positive cores, negative proximals, distals are greater, positive proximals are less than, the randoms. This suggests that the real CACA elements are likely active or activable.

Acknowledgements

The content on this page was first contributed by: Henry A. Hoff.

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Ilaria M. C. Orlando, Véronique N. Lafleur, Federica Storti, Patrick Spielmann, Lisa Crowther, Sara Santambrogio, Johannes Schödel, David Hoogewijs, David R. Mole, and Roland H. Wenger (19 December 2019). "Distal and proximal hypoxia response elements co-operate to regulate organ-specific erythropoietin gene expression". Haematologica. 105 (12): 2774–2784. doi:10.3324/haematol.2019.236406. PMID 33256376 Check |pmid= value (help). Retrieved 6 May 2021.

External links


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