For species which use divergent chromosomes (such as X and Y) to determine sex, equalization of sex chromosome gene expression is the most immediate and vital aspect of sexual differentiation. This is termed dosage compensation, and in Drosophila it is achieved by a two- fold up regulation of X-linked genes in the male. The large, non-coding roX1 and roX2 RNAs (RNA on the X) share features suggesting a role in this process, the most striking of which is that both transcripts bind along the length of the male X chromosome. The long term objective of this project is to understand the mechanism by which a chromosome is selectively compensated. Proposed experiments focus on the role of roX RNAs. Initially the genetic interactions between roX1 and roX2, and between these genes and the male-specific lethals (msls), which are required for compensation, will be determined (Specific Aim I). The roX genes are positively regulated by the msls, revealing a previously unknown aspect of the msls function. Regulation of the roX genes will be further explored in Specific Aim II. The products of the msls bind to the male X chromosome as a ribonucleoprotein complex.
In Specific Aim III the RNA component of the msls complex, which may include known roX RNAs, will be characterized.
Specific Aims III and IV initiate a search for new members of the roX gene family. This information is vital to understanding the function of these RNAs. In contrast to Drosophila, compensation in humans involves inactivation of one of the female X chromosomes. However, both organisms appear to use similar mechanisms, such as histone acetylation, to modify transcription. Additionally, both species selectively coat the modified chromosome with RNA. The large Xist transcript binds to the length of the inactivated X in mammalian females, and is essential for the process of inactivation. These similarities suggest that understanding the mechanism of dosage compensation in Drosophila has relevance to other systems of global transcriptional regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM058427-01
Application #
2725215
Study Section
Genetics Study Section (GEN)
Project Start
1999-01-01
Project End
2003-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Tufts University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
073134835
City
Medford
State
MA
Country
United States
Zip Code
02155
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Deng, Xinxian; Meller, Victoria H (2009) Molecularly severe roX1 mutations contribute to dosage compensation in Drosophila. Genesis 47:49-54
Menon, Debashish U; Meller, Victoria H (2009) Imprinting of the Y chromosome influences dosage compensation in roX1 roX2 Drosophila melanogaster. Genetics 183:811-20
Deng, Xinxian; Meller, Victoria H (2006) roX RNAs are required for increased expression of X-linked genes in Drosophila melanogaster males. Genetics 174:1859-66
Park, Yongkyu; Oh, Hyangyee; Meller, Victoria H et al. (2005) Variable splicing of non-coding roX2 RNAs influences targeting of MSL dosage compensation complexes in Drosophila. RNA Biol 2:157-64
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Park, Yongkyu; Mengus, Gabrielle; Bai, Xiaoying et al. (2003) Sequence-specific targeting of Drosophila roX genes by the MSL dosage compensation complex. Mol Cell 11:977-86
Meller, Victoria H (2003) Initiation of dosage compensation in Drosophila embryos depends on expression of the roX RNAs. Mech Dev 120:759-67
Park, Yongkyu; Kelley, Richard L; Oh, Hyangyee et al. (2002) Extent of chromatin spreading determined by roX RNA recruitment of MSL proteins. Science 298:1620-3
Meller, Victoria H; Rattner, Barbara P (2002) The roX genes encode redundant male-specific lethal transcripts required for targeting of the MSL complex. EMBO J 21:1084-91