? Cornelia de Lange Syndrome (CdLS) is a congenital multisystem disorder marked by facial abnormalities, upper limb defects, hirsutism, gastrointestinal defects, cognitive delays and retarded growth. Recently mutations in the gene NIPBL were found to cause CdLS, providing the first clue to the molecular basis for clinically heterogeneous disease. The NIPBL protein is homologous to the Drosophila melanogaster protein, Nipped-B, which participates in gene activation by remote enhancers. I have uncovered an interaction between NIPBL and the heterochromatin protein 1 family (HP1) that provides the first defined molecular association for NIPBL and points to a possible biological role for NIPBL in chromatin-based gene regulation. In addition, both NIPBL and HP1 homologs in yeast have roles in sister chromatid cohesion, which keeps duplicated chromosomes together until mitosis. Two major types of chromatin have been distinguished, heterochromatin and euchromatin, which serve to organize eukaryotic genomes into functional domains. Such domains are heritable and function at an epigenetic level; that is they are independent of the underlying DNA sequence but are highly dependent on chromatin protein complexes. Epigenetic gene regulation is frequently employed during development and is essential for cell homeostasis. The main features of heterochromatin are silenced genes, condensed DNA and the presence of the HP1 protein. HP1 is a dose dependent regulator of epigenetic gene silencing and reductions in HP1 can lead to abnormal cell growth. We propose that NIPBL and HP1 form a complex that regulates gene expression and this function is disrupted in CdLS individuals. We will test this hypothesis by determining whether NIPBL affects HP1 activity in established assays for HP1 gene silencing in human and mouse cells with mutant NIPBL. We will also localize and isolate NIPBL-HP1 complex in cells and examine chromatin structure for those genes that are co-regulated by HP1 and NIPBL. These studies will lead to a better understanding of the molecular defects arising from NIPBL mutation in CdLS and initiates an important study that potentially exemplifies complex diseases that have roots in loss of epigenetic control during development. ? ? ? ?

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-GTIE-A (01))
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Oster-Granite, Mary Lou
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Drexel University
Schools of Arts and Sciences
United States
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Chatfield, Kathryn C; Schrier, Samantha A; Li, Jennifer et al. (2012) Congenital heart disease in Cornelia de Lange syndrome: phenotype and genotype analysis. Am J Med Genet A 158A:2499-505
Zhang, Zhe; Liu, Jinglan; Kaur, Maninder et al. (2012) Characterization of DNA methylation and its association with other biological systems in lymphoblastoid cell lines. Genomics 99:209-19
Schrier, Samantha A; Sherer, Ilana; Deardorff, Matthew A et al. (2011) Causes of death and autopsy findings in a large study cohort of individuals with Cornelia de Lange syndrome and review of the literature. Am J Med Genet A 155A:3007-24
Liu, Jinglan; Zhang, Zhe; Bando, Masashige et al. (2010) Genome-wide DNA methylation analysis in cohesin mutant human cell lines. Nucleic Acids Res 38:5657-71
Mannini, Linda; Liu, Jinglan; Krantz, Ian D et al. (2010) Spectrum and consequences of SMC1A mutations: the unexpected involvement of a core component of cohesin in human disease. Hum Mutat 31:5-10
Liu, Jinglan; Feldman, Rachel; Zhang, Zhe et al. (2009) SMC1A expression and mechanism of pathogenicity in probands with X-Linked Cornelia de Lange syndrome. Hum Mutat 30:1535-42
Kawauchi, Shimako; Calof, Anne L; Santos, Rosaysela et al. (2009) Multiple organ system defects and transcriptional dysregulation in the Nipbl(+/-) mouse, a model of Cornelia de Lange Syndrome. PLoS Genet 5:e1000650
Inoue, Akira; Hyle, Judith; Lechner, Mark S et al. (2008) Perturbation of HP1 localization and chromatin binding ability causes defects in sister-chromatid cohesion. Mutat Res 657:48-55