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Position-effect variegation in Drosophila: a genetic and molecular approach of epigenetic silencing

English title Position-effect variegation in Drosophila: a genetic and molecular approach of epigenetic silencing
Applicant Spierer Pierre
Number 127431
Funding scheme Project funding (Div. I-III)
Research institution Département de Génétique et Evolution Faculté des Sciences Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Genetics
Start/End 01.10.2009 - 31.07.2013
Approved amount 375'000.00
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Keywords (6)

drosophila; epigenetic silencing; position-effect variegation; heterochromatin; molecular genetics; position effect variegation

Lay Summary (English)

Lead
Lay summary
The precise control of gene activity is essential for the development, the life and the reproduction of living organisms. One of a number of mechanisms of control of gene activity is the permanent inactivation of chromosomes, or domains of chromosomes. Examples include X-chromosome inactivation and genomic imprinting in mammals, and possibly the control of group of genes determining the architect plan of animals. In the fruitfly Drosophila, we have identified and characterized SU(VAR)3-7 as a protein participating in chromosome silencing. Over-expression of SU(VAR)3-7 in vivo triggers the formation of heterochromatin (an inactive state of the chromosome). We have also observed that the effect is stronger for the male X chromosome, the chromosome hyper-activated in males for dosage compensation, and that mutant in dosage compensation suppresses the effect of mutants of the gene encoding SU(VAR)3-7. This observation links two phenomena previously viewed as independent. We conclude that SU(VAR)3-7 plays a crucial role in forming the silenced part of the genome by participating in its condensation into inactive heterochromatin, and that this mechanisms interacts with the process equalizing genetic activity between males and females. Fundamental research in epigenetic silencing provides insight in basic genetic mechanisms involved in human diseases, and in particular in cancer.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
JIL-1 and Su(var)3-7 Interact Genetically and Counteract Each Other's Effect on Position-Effect Variegation in Drosophila
Huai Deng* Weili Cai* Chao Wang* Stephanie Lerach* Marion Delattre† Jack Girton* Jørgen Johans (2010), JIL-1 and Su(var)3-7 Interact Genetically and Counteract Each Other's Effect on Position-Effect Variegation in Drosophila, in Genetics, 185(4), 1183-1192.
Sumoylation of Drosophila SU(VAR)3-7 is required for heterochromatic function
Reo E, Seum, C Spierer P, Bontron S (2010), Sumoylation of Drosophila SU(VAR)3-7 is required for heterochromatic function, in Nucleic Acids Research, 38(13), 4254-4262.

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Responsabilité du service de transfert de connaissance et de technologie de 'Université 02.10.2009 Genève, Switzerland Spierer Pierre;
Responsabilité du service de transafert de technologie de l'UNIGE en tant que Vice-Recteur 02.10.2009 Genève, Suisse, International, Switzerland Spierer Pierre;


Associated projects

Number Title Start Funding scheme
112535 Position-effect variegation in drosophila: a genetic and molecular approach of epigenetic silencing 01.04.2006 Project funding (Div. I-III)

Abstract

Position-effect variegation in Drosophila: A genetic and molecular approach of epigenetic silencingSummary of the proposalBackground. Epigenetics, the study of heritable changes in gene function occurring without a change in the DNA sequence, is a major new field in life sciences. Drosophila has led the way with work starting almost a century ago with position-effect variegation (PEV), a phenomenon of mosaic expression of genes relocated near heterochromatin by a chromosomal rearrangement. Genetic modifiers of PEV have identified essential components of heterochromatin-induced epigenetic silencing as predicted by Reuter and Spierer (1992). We have molecularly identified a number of modifiers of PEV and devoted a lot of work to one of them SU(VAR)3-7. We have revealed that SU(VAR)3-7 participates with other partners in the building of heterochromatin resulting in gene silencing. We have characterized its function by analysing the phenotypes of Su(var)3-7 mutation and over-expression in soma, dissected the different domains of the protein and described its implication in heterochromatin formation as well as it requirement for proper dosage compensation. We plan to pursue our study of SU(VAR)3-7 function with different partners in different pathways. We will also examine the function of the protein in the gonads, find its genomic targets and its interactors particularly in germ cells. In parallel, we will study methyltransferases responsible of H3K9 methylation, as we have produced essential tools, notably null mutations of dG9a and DmSetDB1 by homologous recombination.Aim 1: Exploring transposable elements as targets of SU(VAR)3-7 in heterochromatin. We have found that SU(VAR)3-7 controls the activity of a number of transposable elements (TEs). We plan to describe the effects of Su(var)3-7 mutations on TEs silencing, and the subsequent effects on their transposition. We plan to unravel the mechanisms of action by examining the expected physical association of the protein on TEs and its possible role controlling this part of the genome potentially detrimental. Finally, we showed genetic interaction between Su(var)3-7 and the small interfering RNAs pathways. It is of importance to study the link between the function of SU(VAR)3-7 and the role of small RNAS in genomic silencing, and the implication of other Su(var) genes in TEs silencing. Aim 2: Exploring the role of SU(VAR)3-7 and its heterochromatic partners in gonads. After a comprehensive analysis of SU(VAR)3-7 physiology in the soma, we plan to describe in details the phenotypes of Su(var)3-7 mutations in gonads, among them an unsumoylable SU(VAR)3-7, notably on chromosome integrity and inheritance, oocyte differentiation, genomic silencing, and regulation of TEs activity. We will expand our study to other factors of the chromatin as the H3K9 HMTase dG9a and DmSETDB1 and other Su(var) genes. Aim 3: Analyzing the function of DmSETDB1. We will describe in details the function of DmSETDB1 in the female gonad and test the effect of its targeting to specific promoters. In parallel, we will study the post-translational ubiquitination of DmSETDB1 and characterize its partners. DmSETD1 appears as an important chromatin regulator, and the work in progress should unravel a comprehensive picture of the mechanisms and targets of silencing.Expected Value. We will demonstrate the importance of several actors of gene silencing in epigenetic control of gene expression, in the regulation of TEs, and in chromosome integrity and segregation at mitosis and meiosis. We want to foster this analysis with a special emphasis on the female gonad. In addition to contributing to the expanding field of epigenetics in biology and human diseases, we expect that our work will bring novel understanding on the so far poorly explored role of epigenetic mechanisms in germline differentiation.
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