Cell type specific transcription is achieved through the integration of regulatory inputs from multiple classes of cis-regulatory elements, such as enhancers, silencers and insulators. Insulators are the class of cis-regulatory elements that establish transcriptional fidelity through the formation of topological domains, which prevent enhancers and silencers from interacting with non-target promoters. Defects in insulator function have been identified in cancers, imprinting syndromes, and repeat expansion diseases, highlighting the importance of insulator function in transcriptional regulation. Mounting evidence suggests that insulator-binding proteins are multi-functional regulators, serving as transcriptiona activators and repressors and contributing to non- transcriptional functions, such as DNA replication. The challenge in the field is to determine how a single insulator protein mediates such diverse regulation and whether a role in chromosome architecture unifies all functions. We address this question through studies of the Drosophila Suppressor of Hairy-wing insulator protein, a multi-functional twelve zinc finger DNA binding protein.
Three aims are proposed. First, we will determine how Su(Hw) establishes insulator function. Second, we will define how genomic context of an Su(Hw) binding sites influences Su(Hw) transcriptional functions. Third, we will establish the requirements for Su(Hw) in chromosome structure and DNA replication. These investigations will elucidate how a single insulator-binding protein confers multiple regulatory outputs. Information gained from these studies will establish a paradigm for understanding mechanisms involved in transcriptional regulation by the human multivalent insulator-binding protein, CCCTC binding factor.

Public Health Relevance

Insulators are cis-regulatory elements critical for transcriptional fidelity. Loss of insulator function may contribute to many human diseases, as mutations in cis-regulatory elements often have a lower burden on fitness than coding mutations. Our studies will define mechanisms of insulator action, which will improve our understanding of how sequence variation in insulators may lead to changes in gene expression and contribute to human disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Special Emphasis Panel (ZRG1)
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Carter, Anthony D
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University of Iowa
Schools of Medicine
Iowa City
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Soshnev, Alexey A; Baxley, Ryan M; Manak, J Robert et al. (2013) The insulator protein Suppressor of Hairy-wing is an essential transcriptional repressor in the Drosophila ovary. Development 140:3613-23
Hohl, Amber M; Thompson, Morgan; Soshnev, Alexey A et al. (2012) Restoration of topoisomerase 2 function by complementation of defective monomers in Drosophila. Genetics 192:843-56
Soshnev, Alexey A; He, Bing; Baxley, Ryan M et al. (2012) Genome-wide studies of the multi-zinc finger Drosophila Suppressor of Hairy-wing protein in the ovary. Nucleic Acids Res 40:5415-31
Soshnev, Alexey A; Ishimoto, Hiroshi; McAllister, Bryant F et al. (2011) A conserved long noncoding RNA affects sleep behavior in Drosophila. Genetics 189:455-68
Geyer, Pamela K; Vitalini, Michael W; Wallrath, Lori L (2011) Nuclear organization: taking a position on gene expression. Curr Opin Cell Biol 23:354-9
Baxley, Ryan M; Soshnev, Alexey A; Koryakov, Dmitry E et al. (2011) The role of the Suppressor of Hairy-wing insulator protein in Drosophila oogenesis. Dev Biol 356:398-410
Kuhn-Parnell, Emily J; Helou, Cecilia; Marion, David J et al. (2008) Investigation of the properties of non-gypsy suppressor of hairy-wing-binding sites. Genetics 179:1263-73
Soshnev, Alexey A; Li, Xingguo; Wehling, Misty D et al. (2008) Context differences reveal insulator and activator functions of a Su(Hw) binding region. PLoS Genet 4:e1000159
Geyer, Pamela K; Wallrath, Lori L (2007) Heterochromatin: not just for silencing anymore: report of the Eighth International Conference on Drosophila Heterochromatin. Fly (Austin) 1:251-6
Drapeau, Mark David; Cyran, Shawn A; Viering, Michaela M et al. (2006) A cis-regulatory sequence within the yellow locus of Drosophila melanogaster required for normal male mating success. Genetics 172:1009-30

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