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László SIPOS
Head, Principal Investigator
Henrik GYURKOVICS
Senior Scientist
| Izabella BAJUSZ | Postdoc, Staff Scientist |
| Dávid FARKAS | PhD Student |
| Gábor KÁRPÁTI | PhD Student |
| Viktória KISS | PhD Student |
| Tiborné CSENDES | Technician |
| Anita KISS | Technician |
IN SITU DISSECTION OF CIS-ACTING ELEMENTS IN THE BITHORAX-COMPLEX OF DROSOPHILA
Those who study transcriptional regulation in eukaryotes have come to realize that it’s all about chromatin structure. The biochemistry of histone modification is the topic of the day, but it is not clear how these modifications alter nucleosome packing, or how the spatial limits of the modifications are defined. One of the primary systems for study is the long-term and long-range repression imposed by proteins of the Polycomb-Group. We are dissecting the DNA-sites required for Polycomb-Group repression in the natural context of the chromosome. Our emphasis is not on naming the biochemical players, but on defining the logic of how these sites are switched to repressing mode and how repression is imposed on neighboring sequences.
Many genes that respond to developmental cues must maintain their responding states long after the cues have disappeared. In Drosophila, the maintenance of repressed states of many developmentally important genes is accomplished by a protein called POLYCOMB and by interacting proteins of the Polycomb-Group. Homologous proteins are found in mammals, where they appear to have analogous functions. Long-term repression by the Polycomb-Group is accompanied by a change in chromosome structure making it less accessible to transcription factors and polymerases.
Figure 1. Targeting of the Gal4VP16 reporter gene into the bxd PRE results in a segmentally restricted expression pattern of UASeGFP in larval stage.
Figure 2. Removal of about 700 bp region in the bxd PRE results in a significant change in the chromatin structure of the bithorax-complex. The resulting ectopic gene activation leads to the partial transformation of wing towards haltera (compare left and right panels).
The Polycomb-Group proteins act through DNA-sites called Polycomb Response Elements (PREs). The best examples of such sites are in the Drosophila bithorax-complex, a cluster of genes that control segmental differentiation. Although one of these sites (bxd PRE) has been localized to a segment of about 1500 base pairs, it is not yet clear how it regulates the genes of the bithorax-complex, because there are no mutations that surgically target this PRE. Our goal is to use gene conversion to generate a series of small deletions in and around the bxd PRE and to study the consequences for the genes of the bithorax-complex. We hope to learn whether the PRE is required for activation as well as repression, how the element receives its initial cue, and whether it is redundant or cooperative with other such elements in the bithorax-complex. The deletions may permit a functional subdivision of the element, and further conversion experiments will target binding sites for particular Polycomb-Group proteins.
A second Polycomb Response Element (Mcp PRE) in the bithorax-complex is also being dissected by gene conversion and its properties compared.
Selected publications
Sipos, L., Mihaly, J., Karch, F., Schedl, P., Gausz, J. and Gyurkovics, H. (1998). Transvection in the Drosophila Abd-B domain: extensive upstream sequences are involved in anchoring distant cis-regulatory regions to the promoter. Genetics 149(2): 1031-1050.
Mollaaghababa, R., Sipos, L., Tiong, S.Y., Papoulas, O., Armstrong, J.A., Tamkun, J.W. and Bender, W. (2001). Mutations in Drosophila heat shock cognate 4 are enhancers of Polycomb. Proc. Natl. Acad. Sci. U.S.A. 98(7): 3958-3963.
Bajusz, I., Sipos, L., Györgypál, Z., Carrington, E., Jones, R., Gausz, J. and Gyurkovics, H. (2001). The Trithorax-mimic allele of Enhancer of zeste renders active domains of target genes accessible to Polycomb group dependent silencing in Drosophila melanogaster. Genetics 159: 1135-1150.
Sipos, L. and Gyurkovics, H. (2005). Long-distance interactions between enhancers and promoters - The case of the Abd-B domain of the Drosophila bithorax complex. FEBS J. 272: 3253-3259.
Mihaly, J., Barges, S., Sipos, L., Maeda, R., Cleard, F., Hogga, I., Bender, W., Gyurkovics, H. and Karch, F. (2006). Dissecting the regulatory landscape of the Abd- B gene of the bithorax complex. Development 133: 2983-2993.
Sipos, L., Kozma, G., Molnar, E. and Bender, W. (2007). In Situ Dissection of a Polycomb Response Element in Drosophila melanogaster. Proc. Natl. Acad. Sci. U.S.A. 104(30): 12416-12421.
Kozma, G., Bender, W. and Sipos, L. (2008). Replacement of a Drosophila Polycomb Response Element core, and in situ analysis of its DNA motifs. Mol. Genet. Genomics 279(6): 595-603.