Cornelia de Lange syndrome (CdLS) is caused by mutations in genes that control sister chromatid cohesion. CdLS patients show slow pre- and postnatal growth, mental retardation, autistic features and structural abnormalities in limbs and organs. Unexpectedly, model organism studies indicate that the diverse CdLS deficits are caused by effects on expression of genes that control development, rather than defects in chromatid cohesion. The long-term goal of this proposal is to learn how cohesion factors regulate gene expression and development to increase understanding of the etiology of CdLS and related birth defects. The cohesin complex has a ring-like structure and the leading idea is that cohesin mediates cohesion by encircling the sister chromatids. The NIPBL (Nipped-B-Like) protein loads cohesin onto chromosomes, and most CdLS patients have heterozygous loss-of-function NIPBL mutations. These mutations reduce NIPBL by less than 30%, and do not cause cohesion defects. A small fraction of milder CdLS cases are caused by missense mutations in cohesin subunits. These mutations also do not affect cohesion. The most puzzling aspect of CdLS is how such small changes in cohesion factors have such dramatic effects on development. In model organisms, similar small changes alter gene expression and development without altering cohesion. In Drosophila, cohesin binds preferentially to active genes, and differences in binding between cell lines correlate with differences in gene transcription. These data suggest a model in which cohesin encircles active genes where transcription unwinds the chromosome. It is further proposed that cohesin affects transcription by multiple mechanisms. Because cohesin binds so tightly, its association with genes must be controlled dynamically by NIPBL to facilitate transcription. Thus it is proposed that CdLS is caused by changes in cohesin dynamics that alter gene expression. There are strong structural and functional parallels between human and Drosophila cohesion factors. The proposed work will take advantage of the highly amenable Drosophila animal model to elucidate how cohesion factors regulate gene expression. There are three aims: (1) determine how cohesion factors affect transcriptional elongation, gene activation, and insulator function in cells and in vivo, (2) determine how gene expression regulates cohesin binding using chromatin immunoprecipitation, and (3) determine how changes in cohesion factors affect cohesin chromosome-binding dynamics in vivo using fluorescence recovery after photobleaching. It is hoped that insights from these studies will shed light on the mechanisms by which small changes in cohesion factors cause CdLS, and impact the development of diagnostic and therapeutic methods.

Public Health Relevance

This project is to determine how proteins that control the proper division of chromosomes when cells divide also control genes and development in the fruitfly. Changes in the human versions of these proteins cause Cornelia de Lange syndrome (CdLS), a severe developmental disorder. CdLS children display slow growth before and after birth, and are afflicted with mental retardation and defects in limbs and organs such as the heart;by examining how these proteins work in the fruitfly, we will gain knowledge that will aid the search for new methods to diagnose and treat CdLS patients.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Molecular Genetics C Study Section (MGC)
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Krasnewich, Donna M
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Saint Louis University
Schools of Medicine
Saint Louis
United States
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Schaaf, Cheri A; Misulovin, Ziva; Gause, Maria et al. (2013) Cohesin and polycomb proteins functionally interact to control transcription at silenced and active genes. PLoS Genet 9:e1003560
Schaaf, Cheri A; Misulovin, Ziva; Gause, Maria et al. (2013) The Drosophila enhancer of split gene complex: architecture and coordinate regulation by notch, cohesin, and polycomb group proteins. G3 (Bethesda) 3:1785-94
Dorsett, Dale; Merkenschlager, Matthias (2013) Cohesin at active genes: a unifying theme for cohesin and gene expression from model organisms to humans. Curr Opin Cell Biol 25:327-33
Schaaf, Cheri A; Kwak, Hojoong; Koenig, Amanda et al. (2013) Genome-wide control of RNA polymerase II activity by cohesin. PLoS Genet 9:e1003382
Dorsett, Dale (2013) What fruit flies can tell us about human birth defects. Mo Med 110:309-13
Fasulo, Barbara; Deuring, Renate; Murawska, Magdalena et al. (2012) The Drosophila MI-2 chromatin-remodeling factor regulates higher-order chromatin structure and cohesin dynamics in vivo. PLoS Genet 8:e1002878
Dorsett, Dale; Strom, Lena (2012) The ancient and evolving roles of cohesin in gene expression and DNA repair. Curr Biol 22:R240-50
Cunningham, Melissa D; Gause, Maria; Cheng, Yuzhong et al. (2012) Wapl antagonizes cohesin binding and promotes Polycomb-group silencing in Drosophila. Development 139:4172-9
Dorsett, Dale (2011) Cohesin: genomic insights into controlling gene transcription and development. Curr Opin Genet Dev 21:199-206
Fay, Avery; Misulovin, Ziva; Li, Jian et al. (2011) Cohesin selectively binds and regulates genes with paused RNA polymerase. Curr Biol 21:1624-34

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