Claims
- 1. A method of modulating a regulatory state of a cell, comprising:
(a) identifying a point of interdiction within a cis regulatory network specifying a genetic regulatory architecture of a cell, and (b) introducing into a progenitor cell two or more network elements within said network to induce a predetermined series of cis regulatory network interactions resulting in a specified regulatory state of said progenitor cell.
- 2. The method of claim 1, wherein said point of interdiction comprises a cis regulatory module.
- 3. The method of claim 2, wherein said cis regulatory module controls the expression of a transcription activator or repressor.
- 4. The method of claim 3, wherein said transcription activator or repressor lock down or prevent a regulatory state.
- 5. The method of claim 1, wherein said network element comprises a transcription factor.
- 6. The method of claim 5, wherein said transcription factor comprises a transcription activator, a transcription repressor, or combination thereof.
- 7. The method of claim 1, wherein said cis regulatory network comprises cis regulatory modules and transcription factors interconnected through binding activity.
- 8. The method of claim 7, wherein said genetic regulatory architecture of said cell comprises transcription factor interactions within two or more regulatory territories.
- 9. The method of claim 8, wherein said two or more regulatory territories comprise territories selected from the group consisting of a zygote, a primary germ layer, endoderm, mesoderm, ectoderm and a terminally differentiated cell.
- 10. The method of claim 1, wherein said introduction of two or more network elements further comprises expression of a nucleic acid encoding said network elements.
- 11. The method of claim 10, wherein at least one of said two or more network elements bind to a cis regulatory module at a point of interdiction.
- 12. The method of claim 10, wherein said two or more network elements bind to a cis regulatory module at a point downstream from a point of interdiction.
- 13. The method of claim 1, wherein said regulatory state comprises a differentiation state.
- 14. The method of claim 1, wherein said progenitor cell is selected from the group consisting of a zygote, a pluripotent stem cell, a pluripotent lineage specific progenitor, a progenitor cell, and a terminally differentiated cell.
- 15. A method of modulating a regulatory state of a cell, comprising:
(a) identifying a point of interdiction within a cis regulatory network specifying a genetic regulatory architecture of a cellular state, and (b) introducing into a progenitor cell two or more network elements within said network to induce a predetermined series of cis regulatory network interactions resulting in a specified regulatory state of said progenitor cell.
- 16. The method of claim 15, wherein said point of interdiction comprises a cis regulatory module.
- 17. The method of claim 16, wherein said cis regulatory module controls the expression of a transcription activator or repressor.
- 18. The method of claim 17, wherein said transcription activator or repressor lock down or prevent a regulatory state.
- 19. The method of claim 15, wherein said network element comprises a transcription factor.
- 20. The method of claim 19, wherein said transcription factor comprises a transcription activator, a transcription repressor, or combination thereof.
- 21. The method of claim 15, wherein said cis regulatory network comprises cis regulatory modules and transcription factors interconnected through binding activity.
- 22. The method of claim 21, wherein said genetic regulatory architecture of said cell comprises transcription factor interactions within two or more regulatory territories.
- 23. The method of claim 22, wherein said two or more regulatory territories comprise territories selected from the group consisting of a zygote, a primary germ layer, endoderm, mesoderm, ectoderm and a terminally differentiated cell.
- 24. The method of claim 15, wherein said introduction of two or more network elements further comprises expression of a nucleic acid encoding said network elements.
- 25. The method of claim 24, wherein at least one of said two or more network elements bind to a cis regulatory module at a point of interdiction.
- 26. The method of claim 24, wherein said two or more network elements bind to a cis regulatory module at a point downstream from a point of interdiction.
- 27. The method of claim 15, wherein said regulatory state comprises a differentiation state.
- 28. The method of claim 15, wherein said progenitor cell is selected from the group consisting of a zygote, a pluripotent stem cell, a pluripotent lineage specific progenitor, a progenitor cell, and a terminally differentiated cell.
- 29. A cell having a specified regulatory state, comprising a cis regulatory network having a modified genetic regulatory architecture, said modification comprising two or more exogenous transcription factors activating a predetermined series of cis regulatory network interactions, said series of cis regulatory network interactions resulting in a specified non-naturally occurring regulatory state of said cell.
- 30. The cell of claim 29, wherein said cis regulatory network comprises cis regulatory modules and transcription factors interconnected through binding activity.
- 31. The cell of claim 30, wherein said genetic regulatory architecture of said cell comprises transcription factor interactions within two or more regulatory territories.
- 32. The cell of claim 31, wherein said two or more regulatory territories comprise territories selected from the group consisting of a zygote, a primary germ layer, endoderm, mesoderm, ectoderm, and a terminally differentiated cell.
- 33. The cell of claim 29, wherein said exogenous transcription factors comprises a transcription activator, a transcription repressor, or combination thereof.
- 34. The cell of claim 33, wherein said transcription activator or repressor lock down or prevent a regulatory state.
- 35. The cell of claim 29, wherein said modification further comprises expression of a nucleic acid encoding said two or more exogenous transcription factors.
- 36. The cell of claim 29, wherein said regulatory state comprises a differentiation state.
- 37. The cell of claim 29, wherein said cell is selected from the group consisting of a zygote, a pluripotent stem cell, a pluripotent lineage specific progenitor, a progenitor cell, and a terminally differentiated cell.
- 38. A method of diagnosing an individual suffering from a cellular defect, comprising:
(a) measuring an activity or amount of a plurality of cis regulatory network elements in a sample from an individual suspected of having a cellular defect, and (b) comparing a genetic regulatory architecture of said plurality of cis regulatory network elements in said sample to a reference genetic regulatory architecture indicative of a cell or cellular state, wherein a change or similarity in pattern of said activity or amount of said plurality of elements compared to said reference genetic regulatory architecture indicates that said individual has a cellular defect.
- 39. The method of claim 38, wherein said plurality of cis regulatory network elements comprise transcription activators or transcription repressors corresponding to points of interdiction within a cis regulatory network.
- 40. The method of claim 38, wherein said plurality of cis regulatory network elements comprise transcription activators or transcription repressor controlled by cis regulatory modules at points of interdiction within a cis regulatory network.
- 41. The method of claim 38, wherein said genetic regulatory architecture of said plurality of cis regulatory network elements specifies a genetic regulatory architecture of a cell.
- 42. The method of claim 38, wherein said genetic regulatory architecture of said plurality of cis regulatory network elements specifies a genetic regulatory architecture of a cellular state.
- 43. The method of claim 38, wherein said reference genetic regulatory architecture comprises the genetic regulatory architecture of a cell or cellular state selected from the group consisting of a zygote, a primary germ cell, endoderm, a mesoderm, ectoderm, pluripotent stem cell, pluripotent lineage specific progenitor cell, a progenitor cell and terminally differentiated cell.
- 44. The method of claim 38, wherein said reference genetic regulatory architecture is obtained from a normal cell or cellular state.
- 45. The method of claim 44, wherein said comparison comprises a change in pattern indicating a cellular defect.
- 46. The method of claim 38, wherein said reference genetic regulatory architecture is obtained from a cell having a cellular defect.
- 47. The method of claim 46, wherein said comparison comprises a similarity in pattern indicating a cellular defect.
- 48. A method of treating an individual suffering from a cellular defect, comprising:
(a) identifying a point of interdiction within a cis regulatory network specifying a genetic regulatory architecture of a cell or cellular state; (b) introducing into a progenitor cell two or more network elements within said network to induce a predetermined-series of cis regulatory network interactions resulting in a specified regulatory state of said progenitor cell, and (c) implanting said progenitor cell having said specified regulatory state into an individual suffering from a cellular defect under conditions sufficient for viability in an effective amount sufficient to renew a deficient cellular component.
- 49. The method of claim 48, wherein said point of interdiction comprises a cis regulatory module.
- 50. The method of claim 49, wherein said cis regulatory module controls the expression of a transcription activator or repressor.
- 51. The method of claim 48, wherein said network element comprises a transcription factor.
- 52. The method of claim 48, wherein said cis regulatory network comprises cis regulatory modules and transcription factors interconnected through binding activity.
- 53. The method of claim 52, wherein said genetic regulatory architecture of said cell comprises transcription factor interactions within two or more regulatory territories.
- 54. The method of claim 53, wherein said two or more regulatory territories comprise territories selected from the group consisting of a zygote, a primary germ layer, endoderm, mesoderm, ectoderm and a terminally differentiated cell.
- 55. The method of claim 48, wherein said introduction of two or more network elements further comprises expression of a nucleic acid encoding said network elements.
- 56. The method of claim 55, wherein at least one of said two or more network elements bind to a cis regulatory module at a point of interdiction.
- 57. The method of claim 55, wherein said two or more network elements bind to a cis regulatory module at a point downstream from a point of interdiction.
- 58. The method of claim 48, wherein said regulatory state comprises a differentiation state.
- 59. The method of claim 48, wherein said progenitor cell is selected from the group consisting of a zygote, a pluripotent stem cell, a pluripotent lineage specific progenitor, a progenitor cell, and a terminally differentiated cell.
- 60. A method of identifying compounds having differentiation inducing activity, comprising:
(a) contacting a progenitor cell with a test compound under conditions sufficient for inducing a cis regulatory network interaction, and (b) measuring an activity or amount of a plurality of indicators within a cis regulatory network, wherein a specific pattern of said plurality of indicators corresponding to a specified regulatory state indicates that said test compound has differentiation inducing activity.
Parent Case Info
[0001] This application claims benefit of the filing date of U.S. Provisional Application No. 60/384,962, filed May 30, 2002, entitled AT-WILL DIFFERENTIATION OF UNCOMMITTED CELLS USING GENE REGULATORY NETWORKS and which is explicitly incorporated herein by reference in its entirety.
Government Interests
[0002] This invention was made with government support under grant numbers HD-37105 and RR-06591 awarded by the National Institutes of Health. The United States Government has certain rights in this invention.
Provisional Applications (1)
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Number |
Date |
Country |
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60384962 |
May 2002 |
US |