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.


   Polytene Chromosomes (Blue) from a male fly demonstrate the specificity of MSL2 protein (Red) association with 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.


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