Biology subjects

Saltzman, A. L.

Publications and source records attributed to Saltzman, A. L..

3 recordsLinked to original sources

bioRxiv2025

Transgenerational maintenance of H3K27me3 heterochromatin is balanced by chromodomain proteins in Caenorhabditis elegans

The ability to replicate and pass information to descendants is a fundamental requirement for life. In addition to the DNA-based genetic information, modifications of the DNA or DNA-associated proteins can create patterns of heritable gene regulation. Such epigenetic inheritance allows for adaptation without mutation, but its limits and regulation are incompletely understood. Here we developed a C. elegans system to study the transgenerational epigenetic inheritance of H3K27me3, a conserved histone posttranslational modification associated with gene repression. We find that induced alterations of the genome-wide H3K27me3 landscape and the associated fertility defects persist for many generations in genetically wildtype descendants under selective pressure. We uncover that the inheritance of the altered H3K27me3 landscape is regulated by two chromodomain proteins with antagonizing functions, and provide mechanistic insight into how this molecular memory is initiated and maintained. Our results demonstrate that epigenetic inheritance can act as a mutation-independent, heritable mechanism of adaptation. In BriefOzdemir et al. demonstrate that an altered genomic distribution of the histone modification H3K27me3 can be epigenetically inherited across many generations through the activity of HERI-1/SET-32/MES-4, which is antagonized by CEC-6/PRC2 in C. elegans. HighlightsO_LIAltered H3K27me3 landscapes can be inherited for at least 15 generations in C. elegans. C_LIO_LIThe chromodomain proteins CEC-6 and HERI-1 have opposite roles in antagonizing or promoting the maintenance of the altered H3K27me3 landscape. C_LIO_LIH3K23me3 and H3K36me3 replace H3K27me3 to promote the intergenerational and transgenerational inheritance of the altered epigenome. C_LI

genetics↗

bioRxiv2023

Genome-wide profiling reveals a dual role for histone H2A monoubiquitylation at Polycomb-repressed and enhancer chromatin

Histone modifications are an integral component of eukaryotic genome regulation. Polycomb Repressive Complex 1 (PRC1) is responsible for depositing histone H2A lysine 119 monoubiquitylation (H2AK119ub) and can work cooperatively with PRC2-mediated histone H3 lysine 27 trimethylation (H3K27me3) to maintain gene repression. However, H3K27me3-independent functions and roles in gene activation have also been described for PRC1. Thus, the extent to which Polycomb complexes and their corresponding histone modifications function together or independently and the conservation of these roles in different organisms is unclear. Using C. elegans as a model, we investigated the relationship between H2AK119ub and H3K27me3. Here we show that the majority of H2AK119ub and H3K27me3 enrichment across the genome in embryos is distinct, and that the bulk levels of these modifications are regulated independently. We identify many genes related to nervous system development and functionality that have H2AK119ub-enriched promoters and are misregulated in H2AK119ub-deficient mutants, including a subset of genes that are normally H3K27me3-repressed. Surprisingly, we also find an enrichment of H2AK119ub at enhancers, including enhancers proximal to genes which are both up-regulated and down-regulated following the loss of this histone modification. Together, our results indicate a dual role for H2AK119ub in the regulation of both H3K27me3-repressed and enhancer chromatin states.

genomics↗

bioRxiv2018

HERI-1 is a Chromodomain Protein that Negatively Regulates Transgenerational Epigenetic Inheritance

Transgenerational epigenetic inheritance (TEI) is the inheritance of epigenetic information for two or more generations. In most cases, TEI is limited to 2-3 generations. This short-term nature of TEI could be set by innate biochemical limitations to TEI or by genetically encoded systems that actively limit TEI. dsRNA-mediated gene silencing (RNAi) can be inherited in C. elegans (termed RNAi inheritance or RNA-directed TEI). To identify systems that might actively limit RNA-directed TEI, we conducted a forward genetic screen for factors whose mutation enhanced RNAi inheritance. This screen identified the gene heritable enhancer of RNAi (heri-1), whose mutation causes RNAi inheritance to last longer (>20 generations) than normal. heri-1 encodes a protein with a chromodomain and a kinase-homology domain that is expressed in germ cells and localizes to nuclei. In C. elegans, a nuclear branch of the RNAi pathway (nuclear RNAi or NRDE pathway) is required for RNAi inheritance. We find that this NRDE pathway is hyper-responsive to RNAi in heri-1 mutant animals, suggesting that a normal function of HERI-1 is to limit nuclear RNAi and that limiting nuclear RNAi may be the mechanism by which HERI-1 limits RNAi inheritance. Interestingly, we find that HERI-1 binds to genes targeted by RNAi, suggesting that HERI-1 may have a direct role in limiting nuclear RNAi and, therefore, RNAi inheritance. Surprisingly, recruitment of the negative regulator HERI-1 to genes depends upon that same NRDE factors that drive co-transcriptional gene silencing during RNAi inheritance. We therefore speculate that the generational perdurance of RNAi inheritance is set by competing pro- and anti-silencing outputs of the NRDE nuclear RNAi machinery.

genetics↗