Periodic Reporting for period 1 - HOTIMAGE (HOst-Transposon Interactions in the MAle GErmline)
Okres sprawozdawczy: 2023-06-01 do 2025-11-30
Transposable elements (TEs) are mobile DNA sequences that have extensively colonized mammalian genomes, representing up to half of the DNA content. Far from being passive passengers, they are powerful agents of change: over evolutionary timescales, TEs have been repeatedly co-opted to fuel innovation and adaptation. Yet in the short term, they pose a constant threat, as uncontrolled activity undermines genome integrity and cellular function. Indeed, unrestrained TE reactivation is linked to a wide spectrum of pathological states—including infertility, ageing, cancer, and neurological disorders—through both transposition-dependent and -independent mechanisms. Understanding the interplay between host genomes and their TE residents is therefore a central question with profound implications for development, evolution, and disease. Our research focuses on the multilayered surveillance strategies deployed by mammalian cells to restrain—and occasionally domesticate—TEs, and their regulation and requirements in reproduction.
Indeed, reproductive cells represent a critical battlefield for this host–TE interplay. For TEs, germ cells are the gateway to immortality: only insertions in this lineage ensure vertical inheritance and propagation. For the host, however, unchecked germline TE activity is catastrophic, introducing heritable mutations that can compromise reproduction and species fitness. Paradoxically, mammalian germline development involves a programmed phase of epigenetic reprogramming during which DNA methylation—the primary defense against TEs—is erased genome-wide. This transient relaxation permits TE transcription, yet genomic invasion does not occur. If, however, this permissive window extends beyond its natural boundaries, meiosis is compromised, leading to germ cell collapse and infertility.
The HOTIMAGE project seeks to unravel the molecular mechanisms that integrate TEs into the mammalian germline program and to assess their impact on fertility, using the mouse as a model. We aim to elucidate how TEs are distinguished from genes and how the successive phases of spermatogenesis are protected from their deleterious effects. Ultimately, this work will provide a new conceptual framework for the role of TEs in shaping male gamete production, with far-reaching implications for the etiology of fertility disorders.
Indeed, reproductive cells represent a critical battlefield for this host–TE interplay. For TEs, germ cells are the gateway to immortality: only insertions in this lineage ensure vertical inheritance and propagation. For the host, however, unchecked germline TE activity is catastrophic, introducing heritable mutations that can compromise reproduction and species fitness. Paradoxically, mammalian germline development involves a programmed phase of epigenetic reprogramming during which DNA methylation—the primary defense against TEs—is erased genome-wide. This transient relaxation permits TE transcription, yet genomic invasion does not occur. If, however, this permissive window extends beyond its natural boundaries, meiosis is compromised, leading to germ cell collapse and infertility.
The HOTIMAGE project seeks to unravel the molecular mechanisms that integrate TEs into the mammalian germline program and to assess their impact on fertility, using the mouse as a model. We aim to elucidate how TEs are distinguished from genes and how the successive phases of spermatogenesis are protected from their deleterious effects. Ultimately, this work will provide a new conceptual framework for the role of TEs in shaping male gamete production, with far-reaching implications for the etiology of fertility disorders.
During this first funding period, we have made significant progress in 1) defining the epigenetic dynamics of various families of mammalian transposable elements (TEs) in the precursor phase of spermatogenesis, 2) highlighting a new actor in the defense of male fertility agaisnt TEs, and 3) identifying the impact of unleashed TEs on the process of meiosis.
In 1), using whole genome profiling of DNA methylation and TE-associated chromatin marks, we revealed a previously unrecognized hierarchical organization underlying the sequential silencing of various TEs during spermatogenesis. We are now investigating the mechanisms underlying this hierarchy, by investigating transcriptional patterns and nuclear positioning of the different TE families.
In 2), we found that SPIN1 is involved in the silencing of TEs during spermatogenesis and the protection of male fertility, using a combination of approaches in developmental biology, and transcriptomic and epigenomic profiling. Unexpectedly, Spin1-mutant males show spermatogenic defects and molecular features that distinguish them from classically known mutants of TE repression, highlighting a unique position with the TE repression network that operates during spermatogenesis. Final phenotypic and molecular characterization are underway to epistatically position SPIN1 within this network.
In 3), we found that reactivated TEs may not impair meiosis by mobilizing but rather by altering the meiotic landscape and/or initiating ectopic transcription. We are now concluding the precise mapping of all meiotic recombination steps (chromatin definition of meiotic hotspots, double-strand break formation, and repair) and characterizing the nature and coding potential of the aberrant TE-iniated transcripts that are produced in meiotic cells that reactivate TEs.
In 1), using whole genome profiling of DNA methylation and TE-associated chromatin marks, we revealed a previously unrecognized hierarchical organization underlying the sequential silencing of various TEs during spermatogenesis. We are now investigating the mechanisms underlying this hierarchy, by investigating transcriptional patterns and nuclear positioning of the different TE families.
In 2), we found that SPIN1 is involved in the silencing of TEs during spermatogenesis and the protection of male fertility, using a combination of approaches in developmental biology, and transcriptomic and epigenomic profiling. Unexpectedly, Spin1-mutant males show spermatogenic defects and molecular features that distinguish them from classically known mutants of TE repression, highlighting a unique position with the TE repression network that operates during spermatogenesis. Final phenotypic and molecular characterization are underway to epistatically position SPIN1 within this network.
In 3), we found that reactivated TEs may not impair meiosis by mobilizing but rather by altering the meiotic landscape and/or initiating ectopic transcription. We are now concluding the precise mapping of all meiotic recombination steps (chromatin definition of meiotic hotspots, double-strand break formation, and repair) and characterizing the nature and coding potential of the aberrant TE-iniated transcripts that are produced in meiotic cells that reactivate TEs.
These advances deepen our understanding of reproductive biology, broaden the tools for studying reproductive cells, and set the stage for future progress in diagnosing and improving reproductive health