Biology subjects

Harman, A.

Publications and source records attributed to Harman, A..

4 recordsLinked to original sources

bioRxiv2026

Physiologic variation in sperm miRNAs tune embryonic gene regulatory programs and developmental outcomes

Small RNAs delivered by sperm can transmit environmentally regulated, epigenetically inherited phenotypes to offspring, yet the mechanisms by which modest changes in sperm microRNA abundance overcome dilution within the much larger egg to influence embryonic development remain unresolved. Here, we show that physiologically relevant variation in individual sperm miRNAs is sufficient to quantitatively program embryonic gene expression and developmental outcomes. Using parthenogenetic and fertilized embryos, we show that as few as 200 molecules of miR-200c-3p or miR-465c-3p induces reproducible, dose-dependent gene expression responses across defined developmental windows. Parthenogenetic embryos faithfully recapitulate early miRNA-driven gene expression changes observed in fertilized embryos, validating their use for isolating early regulatory mechanisms. We further developed AGO2-REMORA, an RNA adenosine base editor fused to Argonaute2 to map miRNA-mRNA interactions in embryos, revealing that early mRNA repression reflects direct miRNA targeting, while transcriptional changes at later stages arise as secondary consequences of these initial interactions. Furthermore, we show that modest elevation of miR-200c-3p during early development is sufficient to induce transcriptional alterations through early development and produce craniofacial phenotypes in late-stage embryos, recapitulating features of fetal alcohol syndrome associated with paternal alcohol consumption. Together, these findings establish a generalizable framework by which small perturbations in sperm miRNA content quantitatively modulate early gene regulatory programs, triggering cascades that persist throughout development and influence offspring phenotype.

developmental biology↗

bioRxiv2024

Prochlorococcus predation by a globally abundant filter feeder

Prochlorococcus is the most abundant photosynthetic cell on Earth and is critical to primary productivity and biogeochemical cycles of the open ocean. Appendicularians are ubiquitous gelatinous filter-feeding zooplankton that feed on marine microorganisms including Prochlorococcus. However, the details of this feeding interaction are extremely understudied relative to its potential importance in top-down controls on Prochlorococcus. This is the first study to experimentally examine several dimensions of the feeding interaction between cultivated appendicularians and Prochlorococcus. We found that Prochlorococcus retention rates by the appendicularian Oikopleura dioica increased with prey concentration and predator age. We found that appendicularians grazed equally on the two most globally abundant Prochlorococcus ecotypes HLI and HLII and that the presence of larger diatom prey did not change Prochlorococcus retention rates. The quantitative insight and retention rates provided by this study will help fill gaps in models of the marine carbon cycle and marine microbial community dynamics and biogeography, and expand the knowledge of Prochlorococcus ecology. ImportanceAppendicularians are a known predator of picocyanobacteria, but the details of their feeding on the globally abundant picocyanobacterium Prochlorococcus have not been investigated. We quantified Prochlorococcus retention rates over a range of ecologically relevant conditions, which will inform microbial community predictions and carbon flux models and lead to improved understanding of carbon transfer in the ocean, microbial ecology, and microbial communities.

ecology↗

bioRxiv2024

Nuclear actin and DNA replication stress regulate the recruitment of human telomerase to telomeres

The recruitment of telomerase to telomeres is a tightly regulated process which is stimulated by replication stress and mediated by the DNA damage response regulatory kinase ATR. Here, we demonstrate that nuclear filamentous actin is important for telomerase recruitment under endogenous and replication stress conditions in immortal human cells. Inhibition of nuclear actin polymerization decreases the presence of telomerase at telomeres. This process is regulated by both ATR and mTOR kinases, and employs other regulators of actin structure and function, such as WASP, ARP2/3 and myosin. Nuclear filamentous actin serves as a site for telomerase recruitment, which is mediated by telomere tethering on actin fibres in response to replication stress, allowing telomerase to localize to telomeres containing stalled replication forks. Overall, these data demonstrate that, in human cells which express telomerase, telomeric replication stress triggers the recruitment of telomerase to telomeres via a nuclear actin network, enabling telomere length maintenance.

cancer biology↗

bioRxiv2023

The microbiota and immune system non-genetically affect offspring phenotypes transgenerationally

Summary paragraphThe host-microbiota relationship has evolved to shape mammalian processes, including immunity, metabolism, and development1-3. Host phenotypes change in direct response to microbial exposures by the individual. Here we show that the microbiota induces phenotypic change not only in the individual but also in their succeeding generations of progeny. We found that germ-free mice exhibit a robust sebum secretion defect and transcriptional changes in various organs, persisting across multiple generations despite microbial colonization and breeding with conventional mice. Host-microbe interactions could be involved in this process, since T cell-deficient mice, which display defective sebum secretion4, also transgenerationally transmit their phenotype to progeny. These phenotypes are inherited by progeny conceived during in vitro fertilization using germ-free sperm and eggs, demonstrating that epigenetic information in the gametes is required for phenotypic transmission. Accordingly, small non-coding RNAs that can regulate embryonic gene expression5 were strikingly and similarly altered in gametes of germ-free and T cell-deficient mice. Thus, we have uncovered a novel mechanism whereby the microbiota and immune system induce phenotypic changes in successive generations of offspring. This epigenetic form of inheritance could be advantageous for host adaptation to environmental perturbation, where phenotypic diversity can be introduced more rapidly than by genetic mutation.

microbiology↗