Modulation of endogenous gene expression in cells

1. A method of modulating expression of an endogenous cellular gene in a cell, the method comprising the step of:

contacting the cell with a first polynucleotide encoding a first zinc finger protein, wherein the first zinc finger protein is a fusion protein comprising a designed or selected zinc finger protein in operative linkage with a fimctional domain, further wherein the fusion protein binds to a first target site in the gene;

thereby modulating expression of the endogenous cellular gene.

2. The method of claim 1 , wherein the step of contacting further comprises contacting the cell with a second polynucleotide encoding a second zinc finger protein that binds a second target site in the endogenous cellular gene.

3. The method of claim 2 , wherein the first and second target sites are adjacent.

4. The method of claim 3 , wherein the first and second zinc finger proteins are covalently linked.

5. The method of claim 1 , wherein the first zinc finger protein is a fusion protein comprising at least two regulatory domains.

6. The method of claim 3 , wherein the first and second zinc finger proteins are fusion proteins, each comprising a functional domain.

7. The method of claim 6 , wherein the first and second zinc finger proteins are fusion proteins, each comprising at least two functional domains.

8. The method of claim 1 , wherein the cell is selected from the group consisting of an animal cell, a plant cell, a bacterial cell, a protozoal cell, or a fungal cell.

9. The method of claim 8 , wherein the cell is a plant cell.

10. The method of claim 8 , wherein the cell is a mammalian cell.

11. The method of claim 10 , wherein the cell is a human cell.

12. The method of claim 1 wherein the expression of the endogenous cellular gene is repressed.

13. The method of claim 12 , wherein the functional domain is selected from the group consisting of unliganded thyroid hormone receptor (TR), v-erbA, Dax and RBP.

14. The method of claim 1 , wherein the expression of the endogenous cellular gene is activated.

15. The method of claim 14 , wherein the functional domain is ligand-bound thyroid hormone receptor.

16. The method of claim 15 , wherein the ligand is 3,5,3′-tiiodo-L-thyronine (T3).

17. The method of claim 1 wherein the functional domain is a bifunctional domain (BFD).

18. The method of claim 17 , wherein the activity of the bifunctional domain is dependent upon interaction of the BFD with a second molecule.

19. The method of claim 18 , wherein the BFD is selected from the group consisting of thyroid hormone receptor, retinoic acid receptor, estrogen receptor and glucocorticoid receptor.

20. The method of claim 18 , wherein the second molecule is a protein.

21. The method of claim 18 , wherein the second molecule is a small molecule.

22. The method of claim 19 , wherein the second molecule is a small molecule.

23. The method of claim 22 , wherein the small molecule is selected from the group consisting of thyroid hormone (T3), all-trans-retinoic acid, estradiol, tamoxifen, 4-hydroxy-tamoxifen, RU-486 and dexamethasone.

24. The method of claim 1 , wherein sequences encoding the first zinc finger protein are operablylinked to a promoter, and wherein the first polynucleotide is administered to the cell in a lipid:nucleic acid complex or as naked nucleic acid.

25. The method of claim 24 , wherein the promoter is an inducible promoter.

26. The method of claim 1 , wherein sequences encoding the first zinc finger protein are contained in an expression vector and are operably linked to a promoter, and wherein the method further comprises the step of first administering the expression vector to the cell.

27. The method of claim 26 , wherein the expression vector is a viral expression vector.

28. The method of claim 27 , wherein the expression vector is selected from the group consisting of a retroviral expression vector, an adenoviral expression vector, and an AAV expression vector.

29. The method of claim 26 , wherein the promoter is an inducible promoter.

30. The method of claim 1 , wherein the first target site is upstream of a transcription initiation site of the endogenous cellular gene.

31. The method of claim 1 , wherein the first target site is adjacent to a transcription initiation site of the endogenous cellular gene.

32. The method of claim 1 , wherein the first target site is downstream of a transcription initiation site of the endogenous cellular gene.

33. The method of claim 1 , wherein the zinc finger protein comprises an SP-1 backbone.