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.
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.
|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|
|Andreyeva, Evgeniya N; Bernardo, Travis J; Kolesnikova, Tatyana D et al. (2017) Regulatory functions and chromatin loading dynamics of linker histone H1 during endoreplication in Drosophila. Genes Dev 31:603-616|
|Strom, Amy R; Emelyanov, Alexander V; Mir, Mustafa et al. (2017) Phase separation drives heterochromatin domain formation. Nature 547:241-245|
|Kavi, Harsh; Emelyanov, Alexander V; Fyodorov, Dmitry V et al. (2016) Independent Biological and Biochemical Functions for Individual Structural Domains of Drosophila Linker Histone H1. J Biol Chem 291:15143-55|
|Börner, Kenneth; Jain, Dhawal; Vazquez-Pianzola, Paula et al. (2016) A role for tuned levels of nucleosome remodeler subunit ACF1 during Drosophila oogenesis. Dev Biol 411:217-230|
|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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