Biology subjects

Ilbay, O.

Publications and source records attributed to Ilbay, O..

5 recordsLinked to original sources

bioRxiv2026

Prion-induced heritable states in Caenorhabditis elegans

Self-replicating protein conformations can encode persistent epigenetic states that underlie prion diseases and contribute to age-related neurodegenerative disorders in mammals. In fungi, such conformers are transmitted through mitosis and meiosis, enabling robust inheritance of diverse phenotypes. Whether analogous transgenerational protein-based inheritance extends beyond unicellular systems to metazoans remains unknown. Here, we address this question in C. elegans, a genetically tractable, short-lived animal well suited for tracking the transmission of heritable information across generations. We found that a yeast prion domain, when fused to a host protein, induced a heritable altered state that arose at elevated temperatures and persisted across generations at lower temperatures. The emergence of this state depended on known prionogenic yeast repeats, while the state itself was reversible and behaved semi-dominantly in crosses, consistent with a protein-based epigenetic mechanism. These findings provide direct evidence that protein domains capable of adopting self-replicating conformers can encode heritable information in an animal.

genetics↗

bioRxiv2025

A default silencing mechanism restrains stress-induced genes in C. elegans

Inducible gene expression programs require that target genes remain silent until the proper activation signal is received, a hallmark of stress-response pathways. This quiescence is typically assumed to be the default state of stress-inducible genes, maintained without active cellular intervention. Using a forward genetic screen for constitutive activation of inducible heat shock proteins (iHSPs) in C. elegans, we found that the multi-zinc-finger protein ZNF-236 is essential for maintaining iHSP quiescence under normal conditions. Loss of znf-236 causes constitutive iHSP expression throughout the genome, affecting both endogenous iHSP loci and iHSP sequences inserted at dispersed chromosomal sites. However, the effect is also chromosomal context-dependent: robustly heat-responsive iHSP transgenes integrated into the ribosomal DNA locus or extrachromosomal arrays are unaffected by znf-236 loss. This differential responsiveness suggests iHSP induction in znf-236 mutants results from a shift in genome organization, rather than from accumulated denatured proteins or engagement of the canonical heat shock response. Our findings demonstrate the existence of a potent ZNF-236-dependent default silencing mechanism that broadly restrains iHSP genes across the genome and helps ensure appropriate iHSP quiescence even at ectopic chromosomal locations. Contrary to prior assumptions, this suggests that quiescence of stress-inducible genes reflects an actively maintained genomic state rather than merely a passive absence of expression. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/683740v3_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@76b062org.highwire.dtl.DTLVardef@360ac9org.highwire.dtl.DTLVardef@1fe330eorg.highwire.dtl.DTLVardef@1c9ea7d_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2019

Regulation of Nuclear-cytoplasmic Partitioning by the lin-28-lin-46 Pathway Reinforces MicroRNA Repression of HBL-1 to Confer Robust Cell-fate Progression in C. elegans

MicroRNAs target complementary mRNAs for degradation or translational repression, reducing or preventing protein synthesis. In C. elegans, the transcription factor HBL-1 (Hunchback-like 1) promotes early larval (L2) stage cell-fate, and the let-7-family microRNAs temporally down-regulate HBL-1 to enable the L2-to-L3 cell-fate progression. In parallel to let-7-family microRNAs, the conserved RNA binding protein LIN-28 and its downstream gene lin-46, also act upstream of HBL-1 in regulating the L2-to-L3 cell-fate progression. The molecular function of LIN-46, and how the lin-28-lin-46 pathway regulates HBL-1, are not understood. Here, we report that the regulation of HBL-1 by the lin-28-lin-46 pathway is independent of the let-7/lin-4 microRNA complementary sites (LCSs) in the hbl-1 3UTR, and involves a stage-specific post-translational regulation of HBL-1 nuclear accumulation. We find that LIN-46 is necessary and sufficient to prevent nuclear accumulation of HBL-1. Our results illuminate that the robust progression from L2 to L3 cell-fates depends on the combination of two distinct modes of HBL-1 down-regulation: decreased synthesis of HBL-1 via let-7-family microRNA activity, and decreased nuclear accumulation of HBL-1 via action of the lin-28-lin-46 pathway. Like HBL-1, many microRNA targets are transcription factors (TFs); and cooperation between regulation of nuclear accumulation and microRNA-mediated control of synthesis rate may be required to increase the precision of or confer robustness to down-regulation of these microRNA target TFs, which can be critical to achieve the optimal phenotypes.

developmental biology↗

bioRxiv2019

C. elegans LIN-28 controls temporal cell-fate progression by regulating LIN-46 expression via the 5’UTR of lin-46 mRNA

Human Lin28 is a conserved RNA-binding protein that promotes proliferation and pluripotency and can be oncogenic. Lin28 and C. elegans LIN-28 bind to precursor RNAs of the conserved, cellular differentiation-promoting, microRNA let-7 and inhibits production of mature let-7 microRNA. Lin28/LIN-28 also binds to and regulates many mRNAs in various cell types. However, the determinants and consequences of these LIN-28-mRNA interactions are not well understood. Here, we report that LIN-28 in C. elegans represses the expression of LIN-46, a downstream protein in the heterochronic pathway, via the 5 UTR of the lin-46 mRNA. We show that both LIN-28 and the 5UTR of lin-46 are required to prevent LIN-46 expression in the L1 and L2 stages, and that precocious LIN-46 expression is sufficient to skip L2 stage proliferative cell-fates, resulting in heterochronic defects similar to the ones observed in lin-28(0) animals. We propose that the lin-46 5UTR mediates LIN-28 binding to and repression of the lin-46 mRNA. Our results demonstrate that precocious LIN-46 expression alone can account for lin-28(0) phenotypes, demonstrating the biological importance of regulation of individual target mRNAs by LIN-28.

developmental biology↗

bioRxiv2019

Environmental pheromone and endocrine signals correct heterochronic developmental phenotypes caused by insufficient expression of let-7 family microRNAs in C. elegans

Adverse environmental conditions can affect rates of animal developmental progression and lead to temporary developmental quiescence (diapause), exemplified by the dauer larva stage of the nematode Caenorhabditis elegans. Remarkably, patterns of cell division and temporal cell fate progression in C. elegans larvae are not affected by changes in developmental trajectory. However, the underlying physiological and gene regulatory mechanisms that ensure robust developmental patterning despite substantial plasticity in developmental progression are largely unknown. Here, we report that diapause-inducing environmental pheromone and endocrine signals correct heterochronic developmental cell lineage defects caused by insufficient expression of let-7 family microRNAs in C. elegans. Two conserved endocrine signaling pathways, DAF-7/TGF-{beta} and DAF-2/Insulin, that confer on the larva diapause/non-diapause alternative developmental trajectories, interact with the nuclear hormone receptor, DAF-12, to initiate and regulate a rewiring of the genetic circuitry controlling temporal cell fates. This rewiring includes: 1) repression of the DAF-12 ligand-activated expression of let-7 family microRNAs, and 2) engagement of a novel ligand-independent DAF-12 activity to downregulate the critical let-7 family target Hunchback-like-1 (HBL-1). This alternative HBL-1 downregulation program is responsible for correcting let-7 family insufficiency phenotypes and it requires the activities of certain heterochronic genes, lin-46, lin-4 and nhl-2, that are previously associated with an altered genetic program in post-diapause animals. Our results show how environmental pheromones and endocrine signaling pathways can coordinately regulate both developmental progression and cell fate transitions in C. elegans larvae under stress, so that the developmental schedule of cell fates remains unaffected by changes in developmental trajectory.

developmental biology↗