Genetic inheritance material of a living organism (DNA) is stored in chromosomes. Understanding of cellular activities in normal development and disease requires more than the DNA sequence and individual- specific variations of the genome. Critical regulatory roles are also played by packaging of the genome into a conserved nucleoprotein complex termed chromatin. Chromatin is assembled and maintained by a concerted action of two families of proteins, namely histone chaperones and ATP-driven motor chromatin remodeling factors. The structure of chromatin and the regulatory machinery of its metabolism are uniquely important and thus strongly conserved in evolution. The ultimate objective of our work is to understand the relationship between the establishment of chromatin structure and regulation of the function of eukaryotic chromosomes. We will focus on a systematic study of proteins that mediate chromatin assembly. We will analyze elementary molecular events and examine interactions at the interface of histone chaperones and motor factors that take place during chromatin assembly in vitro (in a test tube). In addition, we will investigate specific functional roles for chromatin assembly factors in a living model organism, fruit fly (Drosophila melanogaster). We will perform experiments to understand how the assembly factors alter chromatin structure in vivo and regulate various DNA-directed enzymatic processes, such as transcription, DNA replication and repair. The chromatin of mature sperm differs in composition from normal cell chromatin, in particular by an extraordinary high degree of DNA condensation. Sperm chromatin is enzymatically static and is formed by compaction of DNA with small basic, cysteine-rich proteins termed protamines. At fertilization, the egg faces the challenge of remodeling the condensed sperm chromatin into an accessible, transcription- and replication- competent form. We recently discovered cellular machinery that mediates sperm chromatin remodeling in vitro and in vivo. Thus, we will also study the factors that mediate sperm chromatin remodeling. The successful completion of this project will lead to a comprehensive biochemical and biological characterization of factors that mediate the assembly of various forms of chromatin. More globally, our work will provide insights into the role of chromosome assembly and maintenance in regulation of the cell function and will be applicable to understanding, diagnosis and treatment of human diseases that involve defects in processes of DNA metabolism.

Public Health Relevance

Chromatin is the native form of DNA in human cells and is essential for the maintenance of genome integrity and regulation of DNA metabolism. The goal of this project is to understand the function of protein factors that mediate chromatin assembly. Our work will help to design methods of diagnosis and treatment of human diseases that involve defects in chromosome structure.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics B Study Section (MGB)
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Carter, Anthony D
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Albert Einstein College of Medicine
Anatomy/Cell Biology
Schools of Medicine
United States
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Emelyanov, Alexander V; Rabbani, Joshua; Mehta, Monika et al. (2014) Drosophila TAP/p32 is a core histone chaperone that cooperates with NAP-1, NLP, and nucleophosmin in sperm chromatin remodeling during fertilization. Genes Dev 28:2027-40
Lu, Xingwu; Wontakal, Sandeep N; Kavi, Harsh et al. (2013) Drosophila H1 regulates the genetic activity of heterochromatin by recruitment of Su(var)3-9. Science 340:78-81
Emelyanov, Alexander V; Vershilova, Elena; Ignatyeva, Maria A et al. (2012) Identification and characterization of ToRC, a novel ISWI-containing ATP-dependent chromatin assembly complex. Genes Dev 26:603-14
Morettini, Stefano; Tribus, Martin; Zeilner, Anette et al. (2011) The chromodomains of CHD1 are critical for enzymatic activity but less important for chromatin localization. Nucleic Acids Res 39:3103-15
Podhraski, Valerie; Campo-Fernandez, Beatriz; W├Ârle, Hildegard et al. (2010) CenH3/CID incorporation is not dependent on the chromatin assembly factor CHD1 in Drosophila. PLoS One 5:e10120
Lu, Xingwu; Wontakal, Sandeep N; Emelyanov, Alexander V et al. (2009) Linker histone H1 is essential for Drosophila development, the establishment of pericentric heterochromatin, and a normal polytene chromosome structure. Genes Dev 23:452-65
Konev, Alexander Y; Tribus, Martin; Park, Sung Yeon et al. (2007) CHD1 motor protein is required for deposition of histone variant H3.3 into chromatin in vivo. Science 317:1087-90