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Derepression of Heterochromatin Inactivation by Induction of a Nearby Promoter in Drosophila Melanogaster

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Derepression of Heterochromatin Inactivation by Induction of a Nearby Promoter in Drosophila Melanogaster Graduate Theses, Dissertations, and Problem Reports 1998 Derepression of heterochromatin inactivation by induction of a nearby promoter in Drosophila melanogaster Daniel Renick McNeill West Virginia University Follow this and additional works at: https://researchrepository.wvu.edu/etd Recommended Citation McNeill, Daniel Renick, "Derepression of heterochromatin inactivation by induction of a nearby promoter in Drosophila melanogaster" (1998). Graduate Theses, Dissertations, and Problem Reports. 921. https://researchrepository.wvu.edu/etd/921 This Thesis is protected by copyright and/or related rights. It has been brought to you by the The Research Repository @ WVU with permission from the rights-holder(s). You are free to use this Thesis in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you must obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Thesis has been accepted for inclusion in WVU Graduate Theses, Dissertations, and Problem Reports collection by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. Derepression of heterochromatin inactivation by induction of a nearby promoter in Drosophila melanogaster Daniel R. McNeill Thesis submitted to the Faculty of West Virginia University In Partial Fulfillment of the Requirements for the degree of Master of Science in Cellular and Molecular Biology Clifton P. Bishop, Chair Dan Pannacione Jeff Price December, 1998 Morgantown, West Virginia Keywords: Silencing, Heterochromatin, Position-effect, Development Copyright 1998, Daniel R. McNeill Derepression of heterochromatin inactivation by induction of a nearby promoter in Drosophila melanogaster Daniel R. McNeill Abstract Position-effect variegation (PEV) describes the compaction of a euchromatic gene placed next to a region of heterochromatin. This compaction into heterochromatin in some instances results in a mosaic phenotype in Drosophila melanogaster. Since its discovery in the 1930's the phenomenon of PEV has been extensively analyzed and many models describing the mechanics have been proposed. But, until recently a model system for analyzing the phenomenon at various developmental stages was not available. In 1996, Lu, Bishop, and Eissenberg were able to use a transgenic construct that variegates for both a heat shock 70 promoter-driven lacZ construct and a mini-white gene, to allow more in- depth characterization of the developmental changes inherent in the formation of heterochromatin. The results of their research demonstrated that heterochromatic inactivation of gene expression is subject to a developmentally programmed derepression. Using this same construct, I have further characterized the phenomenon by classically constructing several genetic lines, which were either capable or incapable of initiating a heat shock response, but otherwise genetically identical. These lines were reared in both heat shock and non-heat shock conditions and then variegation was assessed by the amount of eye pigment deposited by the derepression of the mini-white gene. Our results indicate that derepression is a progressive event and that the expression of a nearby gene, Hsp-70 in this experimentation, can facilitate the derepression of nearby genes compressed into heterochromatin. It can be reasoned that this cooperative derepression may be playing a role in the expression of genes contained within B- heterochromatin. In this region there appears to be a dispersal of euchromatic genes around heterochromatic ones. Dedication I dedicate this work to my daughter Zoie Catherine McNeill and my fiancee Lori Paton whose love and beauty have been an inspiration to continue striving to achieve the utmost of my abilities intellectually, emotionally, and spiritually. iii Acknowledgements I would like to thank: Dr. Keith Garbutt for his most thorough assistance in compiling the statistics used in the analysis of this experiment. My committee members; Dr. Jeff Price and Dr. Dan Pannacione for their excellent advice and editing. Mostly, I would like to thank my mentor and chair of my committee, Dr. Clifton P. Bishop whose understanding, compassion, and scholarship was always offered freely. iv Table of Contents Item Page Introduction....................................................................................................................1 Materials and Methods.............................................................................................16 Description and Rearing of Fly Stocks......................................................16 Figure 1: P-element transgene construct..............................................17 Figure 2: Classical Genetics....................................................................18 Classical Genetics........................................................................................19 Temperature Shift Experiments..................................................................19 Eye Pigmentation Determination............................................................20/21 Double Blind Study.......................................................................................21 Results.........................................................................................................................22 Table 1: Red Eye Pigmentation Assay for Cross 1 Males..................23 Table 2: Red Eye Pigmentation Assay for Cross 1 Females.............24 Table 3: Red Eye Pigmentation Assay for Control Cross 2................25 Discussion..................................................................................................................26 References.................................................................................................................32 v Introduction The in-depth study of heterochromatin and its role in the expression of the genes of Drosophila began during the early years of Drosophila genetics. In the yearly reports from TH Morgan's laboratory in the 1920s and 1930s, the discovery of new genetic markers was described, and it was noted that only a few genes mapped to the Y chromosome, the proximal portion of the X chromosome, or the areas surrounding the attachment sites for spindles on the autosomes. So few were mapped to this region, which was latter to be called the heterochromatic portion, that it was called the "inert" region (Schultz, 1939). This reasoning was later found to be flawed as it was discovered that heterochromatin was in fact able to influence gene expression. In 1930, Muller described the repressive effect that heterochromatin can exert on a euchromatic gene. In the course of his experimentation, he discovered several mutations of the white+ (w+) gene that resulted in variegated eye color phenotypes. Each of these mutations was found, after subsequent experimentation, to be the result of placing the euchromatic gene, via chromosomal rearrangement, in close proximity to the heterochromatic portion of the genome (Schultz, 1936). The basic properties of this occurrence were outlined via experimentation centered around the white-mottled (wm) alleles and other mosaic producing rearrangements. It resulted in the coining of the term position effect variegation (PEV) to describe the resultant phenomenon (Lewis, 1950 and Spradling, 1990). These early investigators demonstrated that novel junction-creating breakpoints between heterochromatin and euchromatin could result in the mosaic inactivation of the euchromatic genes, including genes expressed at differing developmental stages and genes which 1 would be expressed in different tissues. The position effects were further shown to be resolved by recombining the gene so that the euchromatic allele was moved away from the euchromatic-heterochromatic breakpoint or by causing a second movement of the variegating allele away from the heterochromatin which fully restored the wild type phenotype. As such, this demonstrated that it was the association with the heterochromatin, and not a mutation in the variegating allele itself, which was responsible for the observed variegating expression. It was also found that a single breakpoint could affect more than one gene, with the strength of the effect diminishing as the distance from the breakpoint was increased. Also, the degree of variegation observed was related to the dose of other heterochromatic regions present in particular, the dosage of the predominantly heterochromatic Y chromosomes present. Thus, by changing the percentage of heterochromatin, as related to euchromatin present in the nucleus, the variegating gene expression could be influenced (Weiler and Wakimoto, 1995, and Spofford, 1976). In 1945, Heitz (1928) introduced the term heterochromatin to describe the regions of the chromosome which remain as deeply staining compacted bodies throughout the cell cycle, including interphase. Thus, the definition of heterochromatin was and still is based mainly on morphological criteria and on the temporal and spatial display of the chromosomes. This allows investigators to use light microscopy to distinguish these regions from those of euchromatin, which is seen to condense at metaphase, but appears to be diffuse during interphase. An interesting point is that the regions which are defined, perhaps erroneously, as being constitutive heterochromatin may change with time and between different
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