Research Interest/Area of Expertise
Genetics, epigenetics, gene regulation, long and short non-coding RNA
Transcriptional control is typically thought of as applying to individual or small groups of genes, but in some cases an entire chromosome may be regulated as a unit. This type of regulation is a common property of sex chromosomes. For example, male fruit flies (Drosophila melanogaster) have a single X chromosome but females carry two X-chromosomes. To correct for the imbalance in the dosage of X-linked genes, Drosophila males transcribe their X chromosome at twice the rate that females do, a process termed dosage compensation. Up-regulation is orchestrated by a complex of proteins that binds selectively to the male X-chromosome and alters chromatin structure and chemistry. These alterations are ultimately responsible for enhanced transcription. The non-coding roX1 and roX2 RNAs, (RNA on the X) participate in formation of this complex and can be observed binding along the length of the X chromosome. Not only do the roX RNAs "paint" the X, but the roX genes are themselves situated on the X chromosome and serve to mark it for compensation. Although dosage compensation is an essential process in male flies, mutations of roX1 are not deleterious to males. We proposed that, in spite of a lack of sequence similarity, roX1 and roX2 fulfilled redundant functions. To test this we generated mutations in roX2 and demonstrated that simultaneous mutation of both roX genes leads to a dramatic decrease in male survival. Work currently underway in my laboratory focuses on the regulatory networks underlying modification of the X chromosome.
A contrasting regulatory process occurs in mammalian females. In mammals, dosage compensation is achieved by silencing one of the two female X-chromosomes. Interestingly, a large untranslated RNA, product of the Xist gene (X inactive-specific transcript) is required for silencing and can be observed coating the silent X chromosome. This surprising convergence between the very different dosage compensation systems of flies and mammals suggests that non-coding RNAs may be common features of chromatin-based gene regulatory systems. Determining the extent of these RNA families and establishing systems to study their regulation and function is critical to our understanding of how they achieve global modulation of gene expression.
Education – Degrees, Licenses, Certifications
- Ph.D. 1990, University of North Carolina, Chapel Hill
Awards and Grants
NIH RO1 GM093110
NIH RO1 GM58427
Wayne State University Research Grant
WSU Bridge Funding
Deshpande, N. and Meller, V.H. (2018) Chromatin that guides dosage compensation is modulated by the siRNA pathway in Drosophila melanogaster. Genetics 209, 1085-1097.
Joshi, S. S. and Meller, V. H. (2017) Satellite repeats identify X chromatin for dosage compensation in Drosophila melanogaster males. Current Biology 27, 1393-1402. Featured article. See linked minireview, Current Biology 27, R378-97.
Larracuente, A. and Meller, V. H. (2016) Male-killers exposed: Spiroplasma hijack essential host machinery. Current Biology 26, R429-R431.
Meller, V. H., Joshi, S.* and Deshpande, N.* (2015) Non-coding RNA and chromatin modification. Annual Review of Genetics 49, 673-95.
Menon, D. U.* and Meller, V. H. (2015) Identification of the Drosophila X chromosome: the long and the short of it. RNA Biology 12, 1088-93.
Koya, S.K.* and Meller, V.H. (2015) Modulation of heterochromatin by Male Specific Lethal proteins and roX RNA in Drosophila melanogaster males. PLoS ONE 10(10): e0140259. doi:10.1371/journal.pone.0140259
Apte, M.* and Meller, V. H. (2015) Sex differences in Drosophila melanogaster heterochromatin are regulated by non-sex specific factors. PLoS ONE 10(6): e0128114.
Menon, D.U.,* Coarfa, C., Xiao, W., Gunaratne, P.H. and Meller, V.H. (2014) siRNAs from an X-linked satellite repeat promote X chromosome recognition in Drosophila melanogaster. PNAS, 111, 16460-65. Recommended by Faculty of 1000.
Joshi, S.,* Cheong, H.* and Meller, V. H. (2014) A strategy for generation and balancing of autosome:Y chromosome translocations. Fly 8, 58-62.
Apte, M.*, Moran, V.#, Menon, D.*, Rattner, B.*, Barry, K. H. #, Zunder, R. #, Kelley, R. and Meller, V. (2014) Generation of a useful roX1 allele by Targeted Gene Conversion. G3 4, 155-162. Cover illustration.
Menon, D. U.* and Meller, V. H. (2012) A role for siRNA in X-chromosome dosage compensation in Drosophila melanogaster. Genetics, 191, 1023-1028.
Menon, D. U.* and Meller, V. H. (2009) Imprinting of the Y chromosome influences dosage compensation in roX1 roX2 Drosophila melanogaster. Genetics 183, 811-20. Featured article.
Deng, X.*, Koya, S. K.*, Kong, Y.* and Meller, V. H. (2009) Coordinated regulation of heterochromatic genes in Drosophila melanogaster males. Genetics 182, 481-91. Featured article.
Deng, X.* and Meller, V. H. (2008) Molecularly severe roX1 mutations contribute to dosage compensation in Drosophila. Genesis 47, 49-54.
Deng, X.* and Meller, V. H. (2006) roX RNAs are required for increased expression of X-linked genes in Drosophila melanogaster males. Genetics 174,1859-1866. Featured article.
Deng, X.*, Rattner, B. P.*, Souter, S. and Meller, V. H. (2005) The severity of roX1 mutations is predicted by MSL localization on the X chromosome. Mechanisms of Development 122, 1094-1105.
Rattner, B. P.* and Meller, V. H. (2004) Drosophila MSL2 protein controls sex-specific expression of the roX genes. Genetics 166, 1825-1832.
Meller, V. H. (2003) Initiation of dosage compensation in Drosophila embryos depends on expression of the roX RNAs. Mechanisms of Development 120, 759-767.
Stuckenholz, C., Meller, V. H. and Kuroda, M. I. (2003) Functional redundancy within roX1, a non-coding RNA involved in dosage compensation in Drosophila. Genetics 164, 1003-1014.
Park, Y., Mengus, G., Bai, X., Kageyama, Y., Meller, V., Becker, P. and Kuroda, M. (2003) Sequence-specific targeting of Drosophila roX genes by the MSL dosage compensation complex. Molecular Cell 11, 977-986.
Park, Y., Kelley, R. L., Oh, H., Kuroda, M. I. and Meller, V. H. (2002) Extent of chromatin spreading determined by roX RNA recruitment of MSL proteins. Science 298, 1620-1623.
Meller, V. H. and Rattner, B.* (2002) The roX genes encode redundant male-specific lethal transcripts required for targeting of the MSL complex. EMBO J. 21, 1084-1091.
Meller, V. H., Gordadze, P., Park, Y., Chu, X., Stuckenholz, C., Kelley, R. L. and Kuroda, M. I. (2000) Ordered assembly of roX RNAs into MSL complexes on the dosage compensated X chromosome in Drosophila. Current Biology 10, 136-143.
Kelley, R., Meller, V. H., Gordadze, P., Roman, G., Davis, R. and Kuroda, M. I. (1999) Epigenetic spreading of the Drosophila dosage compensation complex from roX RNA genes into flanking chromatin. Cell 98, 513-522.
Meller, V. H., Wu, K.-H., Roman, G., Kuroda, M. I. and Davis, R. L. (1997) roX1 RNA paints the X chromosome of male Drosophila and is regulated by the dosage compensation system. Cell 88, 445-457.
Rattner, B. P.* and Meller, V. H. (2004) Worm chromosomes call for recognition! BioEssays, 26, 707-710.
Meller, V. H. (2000) Dosage Compensation: making 1X equal 2X. Trends in Cell Biology 10, 54-59.
Kuroda, M. I. and Meller, V. H. (1997) Transient Xist-ence. Cell 91, 9-11.
Genetics (Bio 3070)