Mitzi Kuroda
Department of Genetics
Harvard Medical School
New Research Building, Room 168
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: (617) 525-4520
Fax: (617) 525-4522
Email: mkuroda@genetics.med.harvard.edu
5 postdoctoral fellows, 1 graduate student
Molecular genetics of dosage compensation in Drosophila.
Epigenetic inheritance of chromatin organization plays a major role in the fidelity of gene expression patterns during development, yet the biochemical mechanisms are not understood. A striking example is dosage compensation, in which X linked gene expression is made equivalent in males (XY) and females (XX). In mammals, this occurs by X-inactivation in females. In contrast, in the fruitfly, Drosophila, dosage compensation increases transcription of X-linked genes in males. In each case, specific molecules bind the X chromosome to remodel its chromatin structure. While gene regulation is generally thought to occur through the function of regulatory proteins, the discoveries of non-coding RNAs that associate along the length of dosage-compensated X chromosomes in mammals and in Drosophila suggest that RNAs can play an intriguing, unexpected role in the regulation of chromatin structure and gene expression.
The dosage compensation complex in Drosophila (composed of non-coding roX RNAs and MSL proteins) is required for site-specific acetylation of histone H4, a modification associated with transcriptional up-regulation. Our studies suggest that initial MSL complex assembly occurs at chromatin entry sites distributed along the length of the X. At least two of these sites encode roX RNAs and these RNAs are thought to be incorporated into the MSL complex at their sites of synthesis. Once assembled with roX RNAs, the MSL complex has the remarkable ability to spread to genes along the chromosome.
These discoveries have provided intriguing parallels between fly and mammalian dosage compensation. The only known participant in X inactivation in mammals is Xist. Xist is a large non-coding RNA that spreads on the inactive X chromosome. Given the potential generality of chromatin regulation by RNA-protein complexes, we are currently focused on the mechanisms by which macromolecular complexes spread in cis, and the specific roles of non-coding RNAs in epigenetic regulation.
References:
- Alekseyenko AA, Larschan E, Lai WR, Park PJ, Kuroda MI. High resolution ChIP-chip analysis reveals that the Drosophila MSL complex selectively identifies active genes on the male X chromosome. Genes Dev. 2006; 20:848-857.
- Larschan E, Alekseyenko AA, Gortchakov AA, Peng S, Li B, Yang P, Workman JL, Park PJ, Kuroda MI. MSL complex is attracted to genes marked by H3K36 trimethylation using a sequence-independent mechanism. Molecular Cell 2007; 28:121-133.
- Alekseyenko AA, Peng S, Larschan E, Gorchakov AA, Lee O-K, Kharchenko P, McGrath SD, Wang CI, Mardis ER, Park PJ, Kuroda MI. A sequence motif within chromatin entry sites directs MSL establishment on the Drosophila X chromosome. Cell 2008; 134:599-609.
- Gorchakov, AA, Alekseyenko, AA, Kharchenko, P, Park, PJ, Kuroda MI. Long range spreading of dosage compensation in Drosophila captures transcribed autosomal genes inserted on X. Genes & Development 2009: 23: 2266-2271.
For a complete listing of publications on PubMed, click here.
BBS webpage updated 6/14/2010