We use dosage compensation in Drosophila as a model to understand how chromatin domains are created and maintained for precise control of gene expression. Dosage compensation increases transcriptional output from the single male X chromosome to balance X and autosomal gene expression in males (XY) as it is in females (XX). This is achieved by the MSL complex, which binds to active genes on the X chromosome, and acetylates histone H4 on Lys 16 within gene bodies. Initial targeting of the X occurs at sites of non-coding roX1 and roX2 RNA synthesis, and at ~250 "chromatin entry sites" through binding to 21 bp MSL recognition elements (MREs) that are enriched, but not exclusive to the X chromosome. A second, sequence-independent "spreading" step leads to binding of virtually all active genes on X in cis. Once bound to gene bodies, the MSL complex somehow increases transcriptional output approximately two-fold. In this proposal, we have developed three specific aims to address the most intriguing aspects of dosage compensation at a mechanistic level.
In Aim 1, we ask how a simple sequence can function specifically on X to nucleate MSL spreading.
In Aim 2, we ask when and how spreading to active genes occurs.
In Aim 3, we ask how the MSL complex increases transcription of X linked genes. Our current approaches reflect the rapid changes in genomic analysis that have occurred in the field. We continue to utilize a model genetic approach, but we can now, for the first time, follow the manipulation of genotype with analysis of the resulting chromosomal and transcriptional phenotypes at very precise, sometimes base pair resolution. Success in these approaches should serve as a model for understanding how the genome is organized for the precise and coordinate regulation of gene expression.
The packaging of the genome into active and silent domains plays a key role in its fidelity in higher organisms, so it is not surprising that aberrations in chromatin-modifying complexes are now recognized to play a crucial role in human diseases, including cancer. Our studies are aimed at understanding how chromatin domains are created and maintained for the precise control of gene expression, using a powerful model system to explore novel insights into epigenetic regulation.
|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|
|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|
|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|
|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|
|Simon, Matthew D; Wang, Charlotte I; Kharchenko, Peter V et al. (2011) The genomic binding sites of a noncoding RNA. Proc Natl Acad Sci U S A 108:20497-502|
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