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Search Results to Rossella Tupler MD, PhD

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Academic Background

Rossella Tupler received her M.D. in 1985 from the University of Brescia, Italy and her Ph.D. in 1990 from the University of Pavia, Italy. In 1993, she completed a specialization in Medical Genetics from the University of Pavia, Italy. Dr. Tupler initially joined the Program in Gene Function and Expression as a visiting scientist in 1996, and has since become a Research Assistant Professor. Dr. Tupler is also an Associate Professor in the Department of Biomedical Sciences at the University of Modena e Reggio Emilia, Italy.

Molecular Pathogenesis of Facioscapulohumeral Muscular Dystrophy

Photo: Rossella Tupler, M.D., Ph.D. Research in my lab focuses on studying the molecular pathogenesis of facioscapulohumeral muscular dystrophy (FSHD), the third most common inherited myopathy. FSHD is characterized by progressive weakness and atrophy of the facial and shoulder girdle muscles, which subsequently spreads to the abdominal and pelvic girdle muscles with highly variable severity. The disease has been causally associated with rearrangements occurring in a tandemly-repeated 3.3 kb unit sequence (termed D4Z4) located in the subtelomeric heterochromatin of chromosome 4 (4q35). In the general population, the size of D4Z4 varies between 11 and 150 units, whereas FSHD patients carry fewer than 11 repeats. The number of D4Z4 repeats is a critical determinant of the age of onset and clinical severity of FSHD.

Multiple lines of evidence indicate that FSHD is not the result of a classical mutation within a protein-coding gene. Instead, the genomic organization of the 4q35 subtelomeric region strongly argues for its role in control of gene expression. Consistent with this hypothesis, we have observed that certain genes mapping at 4q35 are specifically up-regulated in FSHD-affected muscles, and that the extent of transcriptional derepression is a function of the number of deleted D4Z4 repeats. We have further investigated the possibility that deletion of D4Z4 repeats initiates transcriptional misregulation, and have shown that an element within D4Z4 specifically binds a multi-protein complex, called the D4Z4 binding Repressor Complex (DRC), which consists of: YY1, a known transcriptional repressor; HMGB2, an architectural protein; and nucleolin. We have demonstrated that the DRC binds D4Z4 in vitro and in vivo and mediates transcriptional repression of 4q35 genes.

Based upon these results we have proposed that deletion of D4Z4 leads to the inappropriate transcriptional derepression of 4q35 genes resulting in disease (see Figure). In normal individuals, the presence of a threshold number of D4Z4 repeats leads to repression of 4q35 genes by virtue of a transcriptional repressor complex that actively suppresses gene expression. In FSHD patients, deletion of an integral number of D4Z4 repeats reduces the number of bound repressor complexes and consequently decreases (or abolishes) transcriptional repression of 4q35 genes. The model suggests that deletion of repeated elements in the subtelomeric region of 4q may act in cis on neighboring genes by derepressing their transcription and thus initiating a cascade of events that ultimately lead to FSHD. Our studies also provide insights into the biological function of DNA repetitive elements in gene transcription and their potential role in human diseases.

To test the proposed pathogenic model in vivo, we have recently generated transgenic mice over-expressing ANT1, FRG1, and FRG2; these 4q35 genes were found over-expressed in muscle tissues affected by FSHD. We have found that FRG1 transgenic mice develop a muscular dystrophy with features characteristic of the human disease. Interestingly mice over-expressing the FRG1 transgene develop a muscular dystrophy whose degree of severity correlates with the expression level of the transgene. FRG1 is a nuclear protein and several lines of evidence suggest it is involved in pre-messenger RNA splicing. We found that in muscle of FRG1 transgenic mice and FSHD patients, specific pre-mRNAs undergo aberrant alternative splicing. Collectively, our studies suggest that FSHD results from inappropriate overexpression of FRG1 in skeletal muscle, which leads to abnormal alternative splicing of specific pre-mRNAs.

Future plans:

Ongoing research in the lab is aimed at: 1) dissecting the molecular mechanisms controlling gene expression and silencing at 4q35; 2) characterizing genes primarily involved in FSHD pathogenesis; and 3) providing a biological basis for designing therapeutic tools. We expect this research to significantly advance the understanding of the pathogenesis of FSHD and, more generally, to advance the comprehension of the molecular mechanism(s) leading to abnormal transcriptional misregulation.

1. To understand the basis for muscle-specific 4q35 gene over-expression

Altered control of gene expression is an intriguing feature of the pathogenic mechanism of FSHD. Gene activation appears to be muscle-specific, and involves only a subset of 4q35 genes, which are hundreds of kilobases apart, suggesting that several factors and molecular mechanisms may contribute either independently or cooperatively to this phenomenon. Elucidation of these factors will provide important information towards understanding the complex mechanisms controlling tissue-specific gene expression in higher eukaryotes. To elucidate these aspects we will:

  • Characterize the functions of YY1, HMGB2, and nucleolin in muscle cells and identify novel components of the DRC in order to identify tissue-specific factors.
  • Define and functionally characterize the promoter regions of 4q35 genes.
  • Analyze the higher-order chromatin structure at 4q35.

2. To understand the role of 4q35 gene over-expression in the development of FSHD

Our studies indicate that inappropriate expression of 4q35 genes occurs in FSHD muscle and leads to muscular dystrophy. Accordingly, mice over-expressing FRG1, one of the genes up-regulated in FSHD, develop muscular dystrophy in which the degree of severity correlates with the level of expression of the transgene. To fully understand the role of 4q35 gene derepression in the development of FSHD, we aimto:

  • Study the effect of FRG1 expression levels in normal physiology and disease-related processes.
  • Generate and characterize transgenic animals over-expressing multiple 4q35 genes.
  • Generate transgenic animals to define the role of D4Z4 in maintaining chromatin structure.

3. To develop potential therapeutic approaches for treating FSHD.

Our preliminary studies indicate that specific over-expression of 4q35 genes occurs in FSHD muscles. Moreover FRG1 over-expression is sufficient to cause muscular dystrophy in transgenic animals. Collectively, these data argue that the inhibition of FRG1 activity can be considered a therapeutic target for FSHD. To accomplish this goal we will perform high-throughput screening of small molecules using several, diverse assays:

  • FRG1 muscle-specific promoter-Luciferase assay
  • FRG1-differentiation assay
  • FRG1-protein-binding assay

Molecular mechanism for FSHD

Schematic diagram showing the effect of deletion of repetitive elements in 4q35, a hallmark of FSHD, on expression of 4q35 genes (black rectangles). The repeat elements (in yellow) bind YY1 (green), HMGB2 (blue), and nucleolin (red). These proteins form a transcriptional repressor complex that down-regulate expression of 4q35 genes. In FSHD, the number of repeats is reduced to a critical number, resulting in over-expression of genes in the region.

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