Welcome Bender

Department of Biological Chemistry and Molecular Pharmacology
Harvard Medical School
Building C1-203
240 Longwood Avenue
Boston, MA 02115
Tel: (617) 432-1906
Fax: (617) 738-0516

The bithorax complex in the fruit fly is a cluster of “homeotic” genes which confer distinct identities on the different segments of the fly. The genes are strikingly aligned on the DNA in the order of the segments they affect. The genes, and their alignment, are conserved from nematodes to humans. Many of the interactions of bithorax mutations are difficult to explain with the known forms of transcriptional regulation. The paradoxes hopefully reflect novel molecular mechanisms.

The segments of a fly are “numbered” by genes which appear in stripes in the early embryo; these stripes turn on the homeotic genes in the proper positions. After a few hours, the striped gene products disappear, but cells must remember their segmental address. Memory is conferred by a gene called Polycomb. In Polycomb mutants, the homeotic genes turn on everywhere when the stripes fade. Polycomb keeps the homeotic genes appropriately repressed, most likely by altering the chromatin structure.

We have mapped sites to which Polycomb binds, and we have shown that DNA regions repressed by Polycomb are less accessible in-vivo to various DNA binding proteins. We have used gene conversion to mutate these sites in the context of the whole bithorax complex; the resulting flies have dramatic segmental transformations consistent with loss of Polycomb repression. Transcription coming from mobile elements into repressed regions appears to relieve the Polycomb-mediated repression. We suspect that endogenous non-coding transcripts, appearing in the early embryo, might define active or repressed DNA domains in a similar manner. One very large non-coding transcript includes a microRNA precursor. Mutants lacking this miRNA are unable to mate or lay eggs, and they fail to fully repress one homeotic gene in the nervous system. We are currently testing for additional functions of the non-coding RNA’s in the region.

References:

• Fitzgerald, D. P., and W. Bender, Polycomb Group Repression Reduces DNA Accessibility. Mol. Cell. Biol. (2001) 21: 6585-6597.
• Bender, W., and D. P.Fitzgerald, Transcription activates repressed domains in the Drosophila bithorax complex. Development (2002) 129: 4923-4930.
• Ali, J. Y., and Bender W. Cross-Regulation among the Polycomb Group Genes in Drosophila melanogaster. Mol. Cell. Biol. (2004) 24: 7737-7747.
• Sipos, L., Kozma, G., Molnár, E., and W. Bender. In situ Dissection of a Polycomb Response Element in Drosophila melanogaster. Proc. Nat. Acac. Sci. USA (2007) in press.