Roles of non-coding RNAs in gene regulation and chromatin organization

To understand several aspects of gene regulation in eukaryotes, which is achieved by histone modification and chromatin remodeling, our research is focused on understanding the relationship between chromatin organization and non-coding RNAs by studying a model of dosage compensation of the male X chromosome in Drosophila melanogaster. MSL (Male Specific Lethal) complex binds to a male X chromosome and induces 2-fold hypertranscription to equalize the amounts of gene product from one male X chromosome with two female X chromosomes. The MSL complex is composed of at least 6 proteins including two histone modifying enzymes and two non-coding roX (RNA on X) RNAs. Interestingly, the two non-coding roX RNAs, roX1 and roX2, are not only components of the MSL complex, but also are two major MSL spreading initiation sites on the X chromosome. Even though roX1 (3.7 kb) and roX2 (0.5 kb) are very different in size and sequence, they have redundant functions. However, the exact role of these RNAs in targeting and spreading of MSL complex to the male X chromosome is unknown. Therefore, characterization of the function of these roX RNAs will be a key understanding how a RNP (Ribonucleoprotein) complex regulates chromatin organization.

We are currently 1) characterizing functional significance of the alternative splicing of roX RNAs in MSL complex, 2) defining functional domains of roX RNAs and interactions with MSL proteins, 3) analyzing molecular basis of MSL cis-spreading from roX genes, and 4) screening new non-coding RNA(s) interacting with MLE (RNA helicase).

Aging studies with stress resistance in fruitflies

The mechanisms of eukaryotic aging process have not been clearly understood because of its global and epigenetic aspects. However, this aging process should be investigated more thoroughly because it is related to a variety of human diseases such as Alzheimer’s disease. Recent research of the aging process has shown that various signaling pathways are involved in the regulatory mechanisms of aging. These signaling pathways in aging are evolutionarily conserved in different species such as yeast, fruit flies, and mammals. By manipulating temperatures for the embryonic development and aging, cold-blooded animal fruit flies exhibited different responses to stress resistance and longevity.

Our goals are 1) finding genes related to stress resistance and/or longevity, and then 2) analyzing the expressional profiles of those genes and 3) correlating them with changes in stress resistance and/or longevity.

Representative Publications (from 22):

1. Meller VH, Gordadze PR, Park Y, Chu X, Stuckenholz C, Kelley RL, and Kuroda MI. (2000) Ordered assembly of roX RNAs into MSL complexes on the dosage-compensated X chromosome in Drosophila, Curr. Biol., 10(3), 136-143.

2. Park Y and Kuroda MI. (2001) Epigenetic aspects of X-chromosome dosage compensation, Science, 293(5532), 1083-1085.

3. Park Y, Kelley RL, Oh H, Kuroda MI, and Meller VH. (2002) Extent of chromatin spreading determined by roX RNA Recruitment of MSL proteins, Science, 298(5598), 1620-1623.

4. Park Y, Mengus G, Bai X, Kageyama Y, Meller VH, Becker PB, and Kuroda MI. (2003) Sequence-specific targeting of Drosophila roX genes by the MSL dosage compensation complex, Mol. Cell, 11(4), 977-986.

5. Oh H, Park Y, and Kuroda MI. (2003) Local spreading of MSL complexes from roX genes on the Drosophila X chromosome, Genes & Dev., 17(11), 1334-1339.

6. Oh H, Bai X, Park Y, Bone JR, and Kuroda MI. (2004) Targeting dosage compensation to the X chromosome of Drosophila males, Cold Spring Harb Symp Quant Biol., 69, 81-88.

7. Park Y*, Oh H, Meller VH, and Kuroda MI. (2005) Variable splicing of non-coding roX2 RNAs influences targeting of MSL dosage compensation complexes in Drosophila. RNA Biol., 2(4), 157-164. *: Corresponding author

8. An evolutionarily conserved domain of roX2 RNA is sufficient for induction of H4-Lys16 acetylation on the Drosophila X chromosome, Genetics, 177(3), 1429-1437.

9. Stark A, ……, Park Y, ….., Kellis M. (2007) Discovery of functional elements in 12 Drosophila genomes using evolutionary signatures, Nature, 450(7167), 219-232.

10. Park SW, Kuroda MI, and Park Y. (2008) Regulation of histone H4 Lys16 acetylation by predicted alternative secondary structures in roX noncoding RNAs. Mol. Cell. Biol., 28(16), 4952-4962.

11. Spirollari J, Wang JTL, Zhang K, BellofattoV, Park Y, and Shapiro BA. (2009) Predicting consensus structures for RNA alignments via pseudo-energy minimization. Bioinformatics and biology insights, 3, 51-69.

12. Byron K, Cervantes MC, Wang JTL, Lin W, and Park Y. (2010) Mining roX1 RNA in Drosophila genomes using covariance models. International Journal of Computational Bioscience, 1(1), 22-32.

13. Park SW, Oh H, Lin YR, and Park Y. (2010) MSL cis-spreading from roX gene up-regulates the neighboring genes. Biochem. Biophys. Res. Commun., 399, 227-231.

14. Kim K, Lin YR, and Park Y. (2010) Enhancement of stress resistances and downregulation of Imd pathway by lower developmental temperature in Drosophila melanogaster. Experimental Gerontology, 45, 984-987.

15. Lin YR, Kim K, Yang Y, Ivessa A, Sadoshima J, and Park Y. (2011) Regulation of longevity by Regulator of G-protein Signaling (RGS) protein, Loco. Aging Cell, 10, 438-447.

16. Lin YR, Parikh H, and Park Y. (2011) Loco signaling pathway in longevity. Small GTPases, 2, 158-161.