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. 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 and remodeling in the embryo of a model organism, fruit fly (Drosophila melanogaster). We will examine how the activities of histone chaperones and motor factors mediate chromatin assembly in vitro (in a test tube) and investigate their specific functional roles in vivo (in a living organism). Initially, the paternal DNA is presented to a fertilized egg as a specialized nucleoprotein complex. Sperm chromatin differs in composition and structure from the normal cell chromatin, in particular by an extraordinary high degree of DNA condensation. It is enzymatically static and is formed by compaction of DNA with small basic, cysteine-rich proteins termed protamines. Despite its importance for the life cycle of any sexually reproducing organism, sperm chromatin structure has been poorly studied. To fill this gap, we will perform biochemical, biophysical and structural analyses of in vitro reconstituted Drosophila sperm chromatin. 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 (protamine chaperones and enzymes of the thioredoxin system) 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 structure of chromatin and the function of protein factors that mediate chromatin assembly and remodeling. 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, Inc
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Fyodorov, Dmitry V; Zhou, Bing-Rui; Skoultchi, Arthur I et al. (2018) Emerging roles of linker histones in regulating chromatin structure and function. Nat Rev Mol Cell Biol 19:192-206
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Emelyanov, Alexander V; Fyodorov, Dmitry V (2016) Thioredoxin-dependent disulfide bond reduction is required for protamine eviction from sperm chromatin. Genes Dev 30:2651-2656
Xu, Na; Lu, Xingwu; Kavi, Harsh et al. (2016) BEN domain protein Elba2 can functionally substitute for linker histone H1 in Drosophila in vivo. Sci Rep 6:34354
Kavi, Harsh; Lu, Xingwu; Xu, Na et al. (2015) A genetic screen and transcript profiling reveal a shared regulatory program for Drosophila linker histone H1 and chromatin remodeler CHD1. G3 (Bethesda) 5:677-87
Xu, Na; Emelyanov, Alexander V; Fyodorov, Dmitry V et al. (2014) Drosophila linker histone H1 coordinates STAT-dependent organization of heterochromatin and suppresses tumorigenesis caused by hyperactive JAK-STAT signaling. Epigenetics Chromatin 7:16
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

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