Substantial progress has been achieved in recent times in determining the parameters responsible for the activity of individual genes. Less is known concerning the long-standing problem of coordinate gene regulation. We are studying the phenomenon of dosage compensation in Drosophila in order to understand certain novel and essential aspects of eukaryotic gene regulation. Dosage compensation refers to the equalization of most X-linked gene products in males with one X chromosome and one dose of X-linked genes and in females with two X's and two doses of such genes. Since the x chromosome represents a very large proportion of the enchromatic karyotype of Drosophila, dosage compensation is unique among regulatory mechanisms in that it modulates the transcriptional activity of a very large number of genes. Another unique feature of dosage compensation is that it is regulated by well-characterized genes which also control the initial steps in the pathway leading to sexual differentiation. Our experimental goal is to understand the underlying regulatory mechanism(s) of dosage compensation at the molecular level. To this end we propose to achieve the following specific aims: (1) We will identify the X chromosome sequences that enhance the rate of transcription of X-linked genes in males; we will first concentrate on a house-keeping gene (Pgd+) and will return later to the study of Zw+ for comparative purposes. (2) We will identify the regulatory factors responsible for transcriptional enhancement in males. We will use a DNA/protein binding screen and DNA/protein binding assays with X-linked regulatory sequences to identify such regulatory factors. We will also complete the cloning of the regulatory genes msl-l+ and msl-2+ and clone msl-3+. (3) we will search for and characterize new regulatory genes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Mammalian Genetics Study Section (MGN)
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Emory University
Schools of Arts and Sciences
United States
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Cugusi, Simona; Li, Yujing; Jin, Peng et al. (2016) The Drosophila Helicase MLE Targets Hairpin Structures in Genomic Transcripts. PLoS Genet 12:e1005761
Cugusi, Simona; Kallappagoudar, Satish; Ling, Huiping et al. (2015) The Drosophila Helicase Maleless (MLE) is Implicated in Functions Distinct From its Role in Dosage Compensation. Mol Cell Proteomics 14:1478-88
Cugusi, Simona; Ramos, Edward; Ling, Huiping et al. (2013) Topoisomerase II plays a role in dosage compensation in Drosophila. Transcription 4:238-50
Kallappagoudar, Satish; Dammer, Eric B; Duong, Duc Minh et al. (2013) Expression, purification and proteomic analysis of recombinant histone H4 acetylated at lysine 16. Proteomics 13:1687-91
Dunlap, David; Yokoyama, Ruth; Ling, Huiping et al. (2012) Distinct contributions of MSL complex subunits to the transcriptional enhancement responsible for dosage compensation in Drosophila. Nucleic Acids Res 40:11281-91
Morra, Rosa; Yokoyama, Ruth; Ling, Huiping et al. (2011) Role of the ATPase/helicase maleless (MLE) in the assembly, targeting, spreading and function of the male-specific lethal (MSL) complex of Drosophila. Epigenetics Chromatin 4:6
Lucchesi, John C (2009) The structure-function link of compensated chromatin in Drosophila. Curr Opin Genet Dev 19:550-6