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Principal Investigator: Maria Antoninova NINOVA
Organization: UNIVERSITY OF CALIFORNIA RIVERSIDE
Fiscal Year: 2024
Award: $388,750
Funding agency: National Institute of General Medical Sciences
Project Summary
Transposable elements (TEs) are mobile genetic elements that can propagate within the host DNA and have
a significant impact on the genome organization and function. TEs are ubiquitous across the tree of life and
occupy substantial fractions of animal genomes - about 20% of the D. melanogaster, and 45-50% of human and
mouse genomes consist of TE fragments that have accumulated throughout evolution, and active TEs are a
major source of genetic and epigenetic variation. Despite their prevalence, TEs’ unusual characteristics and high
copy numbers left them poorly annotated, and among the most enigmatic and understudied genetic elements.
TEs are typically seen as harmful, as their mobility causes DNA damage and can impact the host genome
and transcriptome by directly disrupting functional elements or introducing ectopic binding sites for transcriptional
and epigenetic regulators. To prevent their deleterious activities, TEs are targeted by various silencing
mechanisms. Among these, the piRNA pathway enforces transcriptional and post-transcription repression of TEs
in animal germlines, which is crucial for fertility and preserving the integrity of genetic information across
generations. On the other hand, TEs are an important source of evolutionary innovation and there is a growing
body of literature on TE-derived regulatory regions and functional products that became incorporated into host
regulatory networks. Interestingly, early embryogenesis of both vertebrates and invertebrates is characterized
by a spike of TE activity, and at least in mice, timely activation of specific TEs is essential for normal
developmental progression. However, the diversity of products from TEs and their functional roles in somatic
cells in both systems remain poorly characterized, largely owing to long-standing technical difficulties in the
genomic analysis of elements that exist in high copy numbers.
The molecular mechanisms of TE regulation and the functional implications of TE activity are central areas
of interest for my laboratory. I present a research program that addresses key questions within two major aspects
of TE biology: 1) the mechanism and regulation of piRNA-mediated TE silencing in the germline and 2) the
characteristics and functions of somatic TE expression during development, using the classic model Drosophila
as a paradigm. First, I propose a focused strategy to dissect the regulation and function of several key piRNA
pathway components, building on my previous findings that protein SUMOylation plays essential roles in piRNA
biogenesis and TE silencing. In parallel, I plan to leverage state-of-the-art long-read and single-cell sequencing
technologies to overcome historical limitations to the genomic analysis of the TE-derived transcriptome, with the
long-term goal of elucidating the molecular basis and functional consequences of somatic TE activity in the
developing organism.
Terms: <Address><Animals><Area><Basic Mechanisms of SUMOylation><Binding Sites><Biogenesis><Biology><Body Tissues><Characteristics><Combining Site><DNA><DNA Alteration><DNA Damage><DNA Injury><DNA Sequence Alteration><DNA Transposable Elements><DNA mutation><Deoxyribonucleic Acid><Development><Drosophila><Drosophila genus><Elements><Embryo><Embryo Development><Embryogenesis><Embryonic><Embryonic Development><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Evolution><Fecundability><Fecundity><Fertility><Gametes><Gene Down-Regulation><Gene Transcription><Generations><Genetic><Genetic Diversity><Genetic Transcription><Genetic Variation><Genetic mutation><Genome><Genomics><Germ Cells><Germ Lines><Germ-Line Cells><Goals><Human Genome><Invertebrata><Invertebrates><Laboratories><Left><Life><Literature><Location><Mediating><Mice><Mice Mammals><Mobile Genetic Elements><Modeling><Molecular><Murine><Mus><Nucleic Acid Regulator Regions><Nucleic Acid Regulatory Sequences><Organism><Origin of Life><Pathway interactions><Pattern><Play><Prevalence><Proteins><RNA Expression><Reactive Site><Regulation><Regulatory Regions><Reproductive Cells><Research><Role><SUMOylation><Sequence Alteration><Sex Cell><Silencer Elements><Silencing Elements><Single cell seq><Somatic Cell><Source><Sumoylation Pathway><System><Technology><Tissues><Transcription><Transcription Repression><Transcriptional Repression><Transcriptional Silencer Elements><Transposable Elements><Trees><Vertebrate Animals><Vertebrates><developmental><epigenetic variation><epigenetically><fruit fly><gene repression><genetic element><genetic information><genetic regulatory element><genomic alteration><global gene expression><global transcription profile><human whole genome><initial cell><innovate><innovation><innovative><interest><living system><mouse genome><pathway><permissiveness><piRNA><piwi RNA><posttranscriptional><preservation><prevent><preventing><programs><sexual cell><single cell next generation sequencing><single cell sequencing><social role><transcriptome><vertebrata>