Epigenetic regulatory processes are critical for the normal development and function of multi-cellular organisms and play an important role in human disease. Facioscapulohumeral muscular dystrophy (FSHD) is the third most common muscular dystrophy. Most FSHD cases are associated with contraction of the number of D4Z4 repeat sequences in the chromosome 4q subtelomeric region (4q-linked FSHD). However, how this repeat contraction leads to disease and the identities of the genes responsible for the disease have not been specifically identified. Using chromatin crosslinking and immunoprecipitation (ChIP), we found that the D4Z4 repeat sequence at the chromosome 4q subtelomeric region (4qter) contains a heterochromatic structure involving histone H3 lysine 9 (K9) trimethylation (H3K9me3) and HP13/cohesin binding. Surprisingly, this structure is specifically lost in 4q-linked FSHD. Furthermore, a similar loss of H3K9me3/HP13/cohesin was observed in the minor population of FSHD cases with no repeat contraction (phenotypic FSHD). Thus, our findings indicate that the loss of H3K9me3/HP13/cohesin at 4qter D4Z4 is a common feature of both types of FSHD. Importantly, HP13/cohesin binding is cell type-specific, suggesting that their roles in cell type-specific chromatin organization possibly explains the cell type-restricted disease phenotype. Furthermore, our preliminary sequence polymorphism analysis suggests that D4Z4 at chromosome 10q also contains a similar organization, which is concomitantly lost in FSHD. This raises the intriguing possibility that the epigenetic change of 4qter D4Z4 can spread to homologous sequences on another chromosome, strongly suggesting that FSHD is an """"""""epigenetic abnormality"""""""" disease. How does this chromatin change at D4Z4 lead to FSHD? Our model is that heterochromatic D4Z4 repeats propagate silenced chromatin structure to other genomic regions through long-distance chromatin interactions that may involve HP13/cohesin. Since our results indicate that D4Z4 is disrupted in FSHD at the level of chromatin structure, deregulation of the downstream target genes may also involve similar chromatin structural changes. Thus, we propose to define the specific epigenetic changes associated with FSHD, and identify disease target genes that are critically regulated by these changes. If successful, the outcome of this study will help to delineate an important gene regulatory pathway that underlies FSHD pathogenesis. The knowledge obtained by this will be useful in designing a strategy to control the pathway and potentially improve dystrophic muscle function. The proposed project should provide novel insight into the role of a specific type of heterochromatin in genome regulation and human health.
Facioscapulohumeral muscular dystrophy (FSHD) is the third most common hereditary muscular dystrophy. We have evidence that FSHD is critically regulated by epigenetic chromatin changes. The proposed project focuses to define this epigenetic change by genome-wide high-throughout mapping and to correlate it with disease phenotype. The outcome of this study will make significant contributions to understanding the molecular mechanism of FSHD as well as to possibly develop therapeutic strategies to improve the physical functioning of FSHD patients. Insight into FSHD may also be applicable to learning more about other muscular dystrophies and inherited diseases.
|Ball Jr, Alexander R; Chen, Yen-Yun; Yokomori, Kyoko (2014) Mechanisms of cohesin-mediated gene regulation and lessons learned from cohesinopathies. Biochim Biophys Acta 1839:191-202|
|Zeng, Weihua; Chen, Yen-Yun; Newkirk, Daniel A et al. (2014) Genetic and epigenetic characteristics of FSHD-associated 4q and 10q D4Z4 that are distinct from non-4q/10q D4Z4 homologs. Hum Mutat 35:998-1010|
|Chien, Richard; Zeng, Weihua; Kawauchi, Shimako et al. (2011) Cohesin mediates chromatin interactions that regulate mammalian Î²-globin expression. J Biol Chem 286:17870-8|
|Chien, Richard; Zeng, Weihua; Ball, Alexander R et al. (2011) Cohesin: a critical chromatin organizer in mammalian gene regulation. Biochem Cell Biol 89:445-58|
|Zeng, Weihua; Ball Jr, Alexander R; Yokomori, Kyoko (2010) HP1: heterochromatin binding proteins working the genome. Epigenetics 5:287-92|
|Wu, Shumin; Wang, Weiping; Kong, Xiangduo et al. (2010) Dynamic regulation of the PR-Set7 histone methyltransferase is required for normal cell cycle progression. Genes Dev 24:2531-42|