Dosage compensation is a striking example of the interplay between gene-specific regulation and chromosomal architecture. This process has evolved to make X-linked gene expression equivalent in males with one X chromosome and females with two. In species examined at the molecular level, dosage compensation is mediated by sex-specific factors that decorate the X chromosomes. In Drosophila, dosage compensation is achieved, at least in part, through site-specific histone H4 acetylation, modulated by a male- specific, X-specific ribonucleoprotein complex composed of MSL proteins and non-coding roX RNAs. Our focus in the coming grant period will be to understand how chromatin activation is targeted and spread along a chromosome. Our current data suggest that sites of noncoding roX RNA synthesis act as nucleation sites for spreading of MSL complexes in cis. Our experiments will test a model for distribution of MSL complexes in which local spreading in cis from roX genes is balanced with diffusion to additional sites in trans. We will analyze the dynamics of MSL complex establishment and maintenance on the X, and autoregulation of roX RNA by MSL complexes. Our model for spreading of MSL complexes raises interesting parallels with mammalian dosage compensation. In both flies and humans, regulatory molecules are normally restricted in cis to the X chromosome, but if brought to autosomes, can spread on genes never before dosage compensated. The organization of chromatin domains by nucleation sites is likely to be an important general mechanism for regulation of genome function. Thus, dissecting the mechanisms underlying these chromatin-based regulatory processes should provide insight into many important biological problems, including normal and disease states in humans. The superb spatial resolution of polytene chromosomes and the availability of mutants in the protein and RNA spreading components make the MSL complex an excellent model system to determine how changes in chromatin architecture affect gene expression in complex organisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM045744-22
Application #
8245208
Study Section
Special Emphasis Panel (NSS)
Program Officer
Carter, Anthony D
Project Start
1991-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
22
Fiscal Year
2012
Total Cost
$437,370
Indirect Cost
$192,345
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Ferrari, Francesco; Alekseyenko, Artyom A; Park, Peter J et al. (2014) Transcriptional control of a whole chromosome: emerging models for dosage compensation. Nat Struct Mol Biol 21:118-25
McElroy, Kyle A; Kang, Hyuckjoon; Kuroda, Mitzi I (2014) Are we there yet? Initial targeting of the Male-Specific Lethal and Polycomb group chromatin complexes in Drosophila. Open Biol 4:140006
Alekseyenko, Artyom A; Gorchakov, Andrey A; Zee, Barry M et al. (2014) Heterochromatin-associated interactions of Drosophila HP1a with dADD1, HIPP1, and repetitive RNAs. Genes Dev 28:1445-60
Ferrari, Francesco; Plachetka, Annette; Alekseyenko, Artyom A et al. (2013) "Jump start and gain" model for dosage compensation in Drosophila based on direct sequencing of nascent transcripts. Cell Rep 5:629-36
Alekseyenko, Artyom A; Ellison, Christopher E; Gorchakov, Andrey A et al. (2013) Conservation and de novo acquisition of dosage compensation on newly evolved sex chromosomes in Drosophila. Genes Dev 27:853-8
Wang, Charlotte I; Alekseyenko, Artyom A; LeRoy, Gary et al. (2013) Chromatin proteins captured by ChIP-mass spectrometry are linked to dosage compensation in Drosophila. Nat Struct Mol Biol 20:202-9
Ferrari, F; Jung, Y L; Kharchenko, P V et al. (2013) Comment on "Drosophila dosage compensation involves enhanced Pol II recruitment to male X-linked promoters". Science 340:273
Zhou, Qi; Ellison, Christopher E; Kaiser, Vera B et al. (2013) The epigenome of evolving Drosophila neo-sex chromosomes: dosage compensation and heterochromatin formation. PLoS Biol 11:e1001711
Strukov, Yuri G; Sural, Tuba H; Kuroda, Mitzi I et al. (2011) Evidence of activity-specific, radial organization of mitotic chromosomes in Drosophila. PLoS Biol 9:e1000574
Kharchenko, Peter V; Alekseyenko, Artyom A; Schwartz, Yuri B et al. (2011) Comprehensive analysis of the chromatin landscape in Drosophila melanogaster. Nature 471:480-5

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