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Gene Regulation Theory: DNA Sequences and Function Control

Unravel the complexity of gene regulation through DNA sequence relationships controlling gene expression, differentiation, and development in a structured model. Discover Connectrons, the key to understanding gene interactions and cellular functions, in this innovative theory of gene regulation. Explore the principles, mechanisms, and hierarchical layers of Connectrons to grasp the orchestrated control of gene expression in diverse organisms.

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Gene Regulation Theory: DNA Sequences and Function Control

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  1. A new theory of gene regulation based on relationships of DNA sequences flanking genes Richard J. Feldmann Global Determinants, Inc. Derwood, Maryland

  2. The intellectual property presented in this talk/document is protected by US and PCT Patent Applications dated May 30,2001

  3. Finding the right question to ask is the hard part • Answering the question is just a matter of hard work.

  4. Have you ever wondered how gene expression is controlled? • The TATA box of a gene is 5’ of the start coding • Small dimeric proteins bind in and near this area • The polymerase assembles around these proteins • Enhancer and/or repressor distal to this area can loop back

  5. Have you ever wondered how cellular differentiation and development is accomplished? • How is gene expression controlled so cells within a tissue are relatively the same? • How in a 1,000 cell creature like C. elegans can all the cells have different functions? • How is cellular development orchestrated?

  6. Simplified Gene Model |<-------------------Promoter----------------->| |<-----Enhancer/Repressor------>|<--TATA Box-->| |<-Beginning of Translation |<--------------Translation Region-------------->| End of Translation----->| + strand ----------------------------------------------------------------------------------------------------------- - strand ----------------------------------------------------------------------------------------------------------- |<-Exon->|<-Intron->|<-Exon->|<-Intron->|<-Exon->| |<-----3'UTR------>| |<--------------------------------------------Gene----------------------------------------------|

  7. Specificity Region • The palindromic specificity area around the TATA box is only 6 to 8 bases in length • 48 = 65,556 is a relatively small number • Not every combination can be used • My sense is that the enhancer/repressor elements only modulate the level of expression

  8. Promoter Action

  9. Range of Gene Numbers • Bacteria have 1,000 to 2,500 genes • S. cervesiae has 6,000 genes • C. elegans has 19,000 genes • A. thaliana has 25,000 genes • H. sapiens has 40,000 genes

  10. How many genes are exposed for promotion at a given time? • If the whole compliment of genes is exposed then quantitative regulatory elements have the whole burden of deciding whether a gene is to be expressed or not

  11. Is there a binary mechanism that could sequestrate genes from promotion? • The promoter regions of sequestrated genes would be hidden from the dimeric initiation proteins • The quantitative regulatory elements would have to deal only with the exposed set of genes

  12. Level 1 Level 2 Six Levels of DNA Structure Level 3 Level 4 Level 5 Level 6

  13. 30 nm Chromatin Structure

  14. Are the level-4 loops random or specific in length? • Is there a sequence specificity to the lengths of these loops? • Could a zinc-finger DNA Binding Protein (DBP) be used to make the loops be specific in length? • Could RNA be used to latch the loops shut?

  15. There are sequence-specific loops! • A simple Fortran program run on yeast showed there are specific sequences on the left and right sides of the level-4 loops • In bacteria, S. servesiae and C. elegans there are not enough DBPs to be able to make a whole-genome mechanism • There are two sequence elements that could be expressed as RNA

  16. Connectron • A left flanking sequence element (T1) of at least 15-bases in length • A right flanking sequence element (T2) of at least 15-bases in length • A pair of sequence elements (C1 and C2) of at least 15-bases in length in the 3’UTR of some gene

  17. Sequence Properties of Connectrons • T1 and T2 have a separation of 0.5kb to 100kb • C1=T1 and C2=T2 • The separation of C1 from C2 is less than 100-bases • The separation of C1/C2 from the end of the gene is less than 1,000-bases

  18. What constraints are placed on the sequences • Only that C1=T1 and C2=T2 • Otherwise any tetrad of non-trivial sequences of at least 15-bases can be used

  19. Connectron Convergence and Divergence • Connectrons form Many-to one relationships • Connectrons form One-to-many relationships

  20. Transient Connectrons • Gene “A” causes some connectron “B” • Some other gene “C” causes a connectron “D” that turns off gene “A” • When gene “C” expresses connectron “B” eventually expires

  21. Permanent Connectrons • Gene “A” causes some connectron “B” but no other connectron ever turns off gene “A”

  22. Hierarchy of Connectrons • Gene “A” causes connectron “B” • Gene “C” causes connectron “D”

  23. Hierarchy of Connectrons • Gene “E” causes connectrons “F” and “G” • Connectron “F” turns off gene “A” which eventually causes connectron “B” to disappear • Connectron “G” turns off gene “C” which eventually causes connectron “D” to disappear

  24. Alternating Layers of a Hierarchy

  25. Full Gene Data for Connectron GN 1361 1 1 1191.213 1191.854 .642 ycfc COG2915 GN 1362 1 1 1191.890 1193.041 1.152 ycfb COG0482 GN 1363 1 1 1193.050 1193.511 .462 b1134 COG0494 GN 1364 1 1 1193.521 1194.144 .624 ymfc COG1187 GP 1365 1 1 1194.346 1195.596 1.251 icda COG0538 TN 1366 1 1 1195.576 1195.597 .022 GC *-* GN 1367 1 1 1196.090 1197.460 1.371 ymfd COG0500 | GP 1368 1 1 1197.918 1198.811 .894 lit - | GN 1369 1 1 1198.902 1200.255 1.354 inte - | GN 1370 1 1 1200.292 1200.603 .312 ymfh - | GP 1371 1 1 1200.675 1201.061 .387 ymfi - | GN 1372 1 1 1200.999 1201.283 .285 ymfj - | GN 1373 1 1 1201.482 1202.156 .675 b1145 COG1974 | GP 1374 1 1 1201.944 1202.447 .504 b1146 - | GP 1375 1 1 1202.479 1203.383 .905 ymfl - | GP 1376 1 1 1203.393 1204.760 1.368 ymfn - | GP 1377 1 1 1204.772 1206.720 1.949 ymfr - | GP 1378 1 1 1206.724 1207.353 .630 ycfk - | GP 1379 1 1 1207.355 1207.768 .414 b1155 - | GN 1380 1 1 1207.740 1208.881 1.142 ycfa - | GP 1381 1 1 1208.908 1209.462 .555 pin COG1961 | GP 1382 1 1 1209.569 1210.402 .834 mcra COG1403 | CN 1383 1 1 1210.756 1210.778 .023 .125 GC * | TN 1384 1 1 1210.756 1210.778 .023 GC *-* CN 1385 1 1 1210.780 1210.801 .022 .102 GC * GN 1386 1 1 1210.903 1211.226 .324 ycgw - GN 1387 1 1 1211.926 1212.330 .405 ycgx - GN 1388 1 1 1212.551 1213.282 .732 ycge COG0789 GN 1389 1 1 1213.487 1214.698 1.212 b1163 COG2200 GP 1390 1 1 1215.012 1215.248 .237 ycgz - GP 1391 1 1 1215.291 1215.563 .273 ymga - GP 1392 1 1 1215.592 1215.858 .267 ymgb -

  26. Gene Abstraction for One-Shot Connectron Group0069 Gene_Name COG_Id Chromosome Direction Start Stop Length ymfd COG0500 1 negative 1196.090 1197.460 1.371 lit - 1 positive 1197.918 1198.811 .894 inte - 1 negative 1198.902 1200.255 1.354 ymfh - 1 negative 1200.292 1200.603 .312 ymfi - 1 positive 1200.675 1201.061 .387 ymfj - 1 negative 1200.999 1201.283 .285 b1145 COG1974 1 negative 1201.482 1202.156 .675 b1146 - 1 positive 1201.944 1202.447 .504 ymfl - 1 positive 1202.479 1203.383 .905 ymfn - 1 positive 1203.393 1204.760 1.368 ymfr - 1 positive 1204.772 1206.720 1.949 ycfk - 1 positive 1206.724 1207.353 .630 b1155 - 1 positive 1207.355 1207.768 .414 ycfa - 1 negative 1207.740 1208.881 1.142 pin COG1961 1 positive 1208.908 1209.462 .555 mcra COG1403 1 positive 1209.569 1210.402 .834 • Genes to be abstracted into Group0069 • Final abstraction • Driving C1/C2 NC 483 1 1 1133.952 1195.596 61.644 Non-Controlled-Gene(s) TN 484 1 1 1195.576 1195.597 .022 *-* GG 485 1 1 1196.090 1210.402 14.312 Group0069 | CNT 486 1 1 1210.756 1210.778 .023 OS-> | TN 487 1 1 1210.756 1210.778 .023 *-* CNP 488 1 1 1210.780 1210.801 .022 --> NC 489 1 1 1210.903 1286.207 75.304 Non-Controlled-Gene(s) CNT 486 1 1 1210.756 1210.778 .023 OS-> |

  27. Transient Connectron • Driving C1/C2 • Transient Connectron • Abstracted Groups

  28. Verbose Description of Transient Connectron

  29. Permanent Connectron • Driving C1/C2 • Permanent Connectron • Abstracted Groups

  30. Virtual Connectron - Example 1 • Driving C1/C2 • Virtual Connectron

  31. Virtual Connectron - Example 2 • Driving C1/C2 • Virtual Connectron

  32. Deeply Nested Connectrons

  33. Geneless Connectrons • There is a class of connectrons that are not associated with any gene - the so-called “geneless connectrons” or more properly “orf-less connectrons” • The geneless connectrons occur in the non-genic portion of a genome. • There are most probably many hierarchies of geneless connectrons for each cell type.

  34. Orf-less Gene Model |<-------------------Promoter----------------->| |<-----Enhancer/Repressor------>|<--TATA Box-->| |<-Beginning of Translation | End of Translation----->| + strand ------------------------------------------------------------- - strand ------------------------------------------------------------- |<-----3'UTR--------->| |<-C1->|--|<-C2->|

  35. Levels of Connectron Structure

  36. SNPs • Connectrons are resistant to single base mutations. • The RNA forming the two Hoogsteen triple-strand helices is often longer than the minimum 15-base length • Any distribution of the C1/C2 length over the minimum is usable. • Mutations just make weaker X-shaped structure.

  37. Tight X Structure Loose X Structure

  38. Connectrons versus Genome Size • The number of genes in a genome is not particularly correlated with the size of the genome. • The size of the genome is linearly correlated with the number of connectrons.

  39. Genome Size vs Connectron Number

  40. Connectrons occur across chromosomes • In a multi-chromosonal genome, C1/C2 sources on one chromosome create connectrons on the same and other chromosomes. • S. cervesiae is a wonderful example.

  41. S. cervesiae cross-chromosome connectron table

  42. Duplicated Fragments • Connectrons are based on the fact that there are duplicated sequences in a genome. • Many fragments have only a few instances • A few fragments have many instances.

  43. Genes per Group • Many groups of genes controlled by connectrons are only one gene. • In S. cervesiae in particular these one-gene groups are the LTR (Long Term Repeats) • A few groups have many genes • The distribution follows an exponential curve

  44. Distribution of C1/C2 distance from last econ • Many C1/C2 connectron sources occur immediately following the last exon • In S. cervesiae some of the C1/C2s are at extreme distances (i.e.10kb) from the last exon with no intervening genes

  45. Distribution of C1/C2 lengths • Many of the C1/C2 fragments are of the minimum length of 15-bases • A few C1/C2s are very long (i.e. over 100-bases in length) • The distribution follows an exponential pattern

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