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

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

Consensus sequences

"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

Promoter occurrences

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 UTRs

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

HRE distal promoters

Negative strand, negative direction: CACGC at 2196, CACGC at 447, CACGC at 379.

Positive strand, negative direction: CACGC at 2207, CACGC at 1991, GCGTG at 1896, GCGTG at 1243, CACGC at 963, GCGTG at 740, CACGC at 663.

Negative strand, positive direction: GCGTG at 2554, GCGTG at 1719, CACGC at 1553, CACGC at 1301, GCGTG at 1242, GCGTG at 1216, CACGC at 1133, CACGC at 1049, GCGTG at 1019, CACGC at 987, CACGC at 969, CACGC at 887, CACGC at 869, CACGC at 803, CACGC at 797, CACGC at 776, GCGTG at 544.

Positive strand, positive direction: GCGTG at 2565, CACGC at 1763, CACGC at 1725, CACGC at 1589, GCGTG at 1555, GCGTG at 1551, CACGC at 1521, GCGTG at 1299, CACGC at 1253, CACGC at 1244, CACGC at 1169, CACGC at 1160, GCGTG at 1135, GCGTG at 1131, CACGC at 1085, GCGTG at 1051, GCGTG at 1047, CACGC at 1017, GCGTG at 977, GCGTG at 877, GCGTG at 799, GCGTG at 795, GCGTG at 685, CACGC at 665, CACGC at 581, CACGC at 497, CACGC at 488.

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.

RDr UTRs

RDr core promoters

RDr proximal promoters

RDr distal promoters

Acknowledgements

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

See also

References

  1. 1.0 1.1 1.2 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