We propose to generate the first high-resolution, comprehensive view of the epigenetic landscape of subtelomeres, the most variable and recombination-prone regions of the human genome. Subtelomeric genes vary markedly in copy number, location, and sequence context among individuals. To fully understand the biological significance of these fast-evolving regions, we will characterize the epigenetic context in which subtelomeric genes operate. In addition to their genomic plasticity, these regions are likely to have unusual chromatin structure due to their proximity to telomeric heterochromatin and abundance of other tandem repeats. We will survey the epigenetic state of many chromosomal ends, but give more attention to subtelomeres with highest relevance to human function and disease. One such region is 4qter, where recurrent contraction of a tandem array, in the context of just one of two structurally variant subtelomeric alleles (4qA), leads to facio-scapulo-humeral dystrophy (FSHD), the third most common inherited muscular dystrophy. This deletion is believed to induce epigenetic changes that cause inappropriate gene expression in 4q or elsewhere, but it is not known how this occurs or what genes are affected.
We aim to identify the genetic and epigenetic features of normal and FSHD-causing 4qA alleles in order to provide a link between the 4q deletion and aberrant muscle function. This work should lead to better diagnosis and counseling of recurrence risk for FSHD patients. We will also focus on regions surrounding WASH genes, which exist in grossly different allelic and paralogous contexts in human subtelomeres. We recently discovered that WASH genes encode a highly conserved, widely expressed, yet previously unrecognized new subfamily of WASP proteins, which reorganize the actin cytoskeleton in response to extracellular signals. To accomplish our goals, we will characterize in detail genomic differences among 4qter alleles and among selected chromosomes carrying WASH, as these regions have very limited representation in the current human genome assembly. For epigenetic profiling, we will develop a microarray covering sequences in and near subtelomeres, regions lacking from other arrays. We will use these arrays to analyze subtelomeres in various cells for chromatin modifications characteristic of repressed and active chromatin. In parallel, we will use FISH to analyze larger-scale epigenetic features of specific WASH or 4q copies, such as nuclear location, chromatin condensation, and matrix association. Finally, we will apply tools capable of distinguishing SNPs and paralogous sequence variants (PSVs) to directly relate epigenetic characteristics with transcriptional activity of specific copies. This research will illuminate the significance of subtelomeric genomics and epigenetics in normal phenotypic variation among humans, as well as in inherited disorders, cancer, and aging. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057070-11
Application #
7491695
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Anderson, Richard A
Project Start
1997-08-01
Project End
2011-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
11
Fiscal Year
2008
Total Cost
$531,021
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Young, Janet M; Whiddon, Jennifer L; Yao, Zizhen et al. (2013) DUX4 binding to retroelements creates promoters that are active in FSHD muscle and testis. PLoS Genet 9:e1003947
Rudd, M Katharine; Endicott, Raelynn M; Friedman, Cynthia et al. (2009) Comparative sequence analysis of primate subtelomeres originating from a chromosome fission event. Genome Res 19:33-41
De Bustos, Cecilia; Ramos, Edward; Young, Janet M et al. (2009) Tissue-specific variation in DNA methylation levels along human chromosome 1. Epigenetics Chromatin 2:7
Raphael, Benjamin J; Volik, Stanislav; Yu, Peng et al. (2008) A sequence-based survey of the complex structural organization of tumor genomes. Genome Biol 9:R59
Linardopoulou, Elena V; Parghi, Sean S; Friedman, Cynthia et al. (2007) Human subtelomeric WASH genes encode a new subclass of the WASP family. PLoS Genet 3:e237
Rudd, M Katharine; Friedman, Cynthia; Parghi, Sean S et al. (2007) Elevated rates of sister chromatid exchange at chromosome ends. PLoS Genet 3:e32
Linardopoulou, Elena V; Williams, Eleanor M; Fan, Yuxin et al. (2005) Human subtelomeres are hot spots of interchromosomal recombination and segmental duplication. Nature 437:94-100
Rowen, Lee; Williams, Eleanor; Glusman, Gustavo et al. (2005) Interchromosomal segmental duplications explain the unusual structure of PRSS3, the gene for an inhibitor-resistant trypsinogen. Mol Biol Evol 22:1712-20
Sebat, Jonathan; Lakshmi, B; Troge, Jennifer et al. (2004) Large-scale copy number polymorphism in the human genome. Science 305:525-8
Fan, Yuxin; Linardopoulou, Elena; Friedman, Cynthia et al. (2002) Genomic structure and evolution of the ancestral chromosome fusion site in 2q13-2q14.1 and paralogous regions on other human chromosomes. Genome Res 12:1651-62

Showing the most recent 10 out of 19 publications