Parental mutations influence wild-type offspring via transcriptional adaptation

Abstract

Transgenerational epigenetic inheritance (TEI) is mostly discussed in the context of physiological or environmental factors. Here, we show intergenerational and transgenerational inheritance of transcriptional adaptation (TA), a process whereby mutant messenger RNA (mRNA) degradation affects gene expression, in nematodes and zebrafish. Wild-type offspring of animals heterozygous for mRNA-destabilizing alleles display increased expression of adapting genes. Notably, offspring of animals heterozygous for nontranscribing alleles do not display this response. Germline-specific mutations are sufficient to induce TA in wild-type offspring, indicating that, at least for some genes, mutations in somatic tissues are not necessary for this process. Microinjecting total RNA from germ cells of TA-displaying heterozygous zebrafish can trigger TA in wild-type embryos and in their progeny, suggesting a model whereby mutant mRNAs in the germline trigger a TA response that can be epigenetically inherited. In sum, this previously unidentified mode of TEI reveals a means by which parental mutations can modulate the offspring’s transcriptome.

Partial sequence identity in a 25-nucleotide long element is sufficient for transcriptional adaptation in the Caenorhabditis elegans act-5/act-3 model

“…The first plasmid [act-3p(long) : rfp] uses a 4 kb promoter for the adapting gene ( act-3 ) to drive TurboRFP expression ( Fig 1A ) [ 4 ]. The second plasmid [eft-3p : act-5(ptc)] uses a ubiquitous promoter to overexpress the mutant gene ( act-5(ptc) ) ( Fig 1B ) [ 11 ]. By analyzing transgenic animals containing one or both of these plasmids ( Fig 1C ), or their derivatives, we can identify the sequence requirements by comparing the RFP expression pattern between control and experimental animals.…”

“…elegans , we have previously reported the ectopic expression of a fluorescent extrachromosomal reporter for act-3 (the adapting gene) in in the intestine of act-5 mutants that display mutant mRNA degradation (i.e., act-5 mutants containing a premature termination codon (PTC) in exon 1) [ 4 ]. In a follow-up study, we reported that expression of an act-5(ptc) transgene ( eft-3p : act-5(ptc) ) leads to increased act-3 mRNA levels as well as the de novo expression of an act-3p : rfp reporter transgene in a tissue where the act-5(ptc) transgene is expressed, namely the uterus [ 11 ]. Here, we use two extrachromosomal transgenes, a TA ‘driver’ (i.e., eft-3p : act-5(ptc) ) and a TA ‘reporter’ (i.e., act-3p : rfp ), to identify sequences on both the mutant transcript and the adapting gene locus that are necessary or sufficient for TA.…”

Reply from Daniel Phillips and Denis Noble

“…This is an interesting discovery and without question repudiates the concept of the Weismann barrier, as they claim, but this is because Acropora corals exhibit gametogenesis from somatic lineages (López-Nandam et al, 2023) and thus have limited bearing on complex animals at the centre of the soma-germline communication debate (but see Reusch et al (2021) for an attempt to integrate such cases into evolutionary theory). We respond to this point not to knit-pick but because it provides an opportunity to mention a case where mutations in zebrafish and C. elegans parents lead to the inheritance of the parental 'transcriptional adaptation' in offspring (Jiang et al, 2022). Here, parents heterozygous for an mRNA destabilising allele exhibited increased 'compensatory' expression of 'adapting' genes, and such transcriptional adaptation was inherited by wild-type offspring, demonstrating a likely ubiquitous mechanism through which acquired changes at the genomic level in parents cause transgenerational reverberations at the transcriptional level likely shaping development phenotypes in the offspring, emphasising the need for a systems perspective of inheritance (Jablonka & Lamb, 2020) Finally, we would like to take this opportunity to point out that although ourselves and the authors have focused on EV RNA and DNA, respectively, circulating nucleic acids need not be associated with EVs at all in order to travel around the body.…”

“…(2021) for an attempt to integrate such cases into evolutionary theory). We respond to this point not to knit‐pick but because it provides an opportunity to mention a case where mutations in zebrafish and C. elegans parents lead to the inheritance of the parental ‘transcriptional adaptation’ in offspring (Jiang et al., 2022). Here, parents heterozygous for an mRNA destabilising allele exhibited increased ‘compensatory’ expression of ‘adapting’ genes, and such transcriptional adaptation was inherited by wild‐type offspring, demonstrating a likely ubiquitous mechanism through which acquired changes at the genomic level in parents cause transgenerational reverberations at the transcriptional level likely shaping development phenotypes in the offspring, emphasising the need for a systems perspective of inheritance (Jablonka & Lamb, 2020)…”

Lifting the cloche: Jeroen Bakkers interviews Didier Stainier

“…Didier: And mammalian cells in culture. We were hoping that C. elegans would allow us to do forward genetic screens, but the transgenerational effects ( Jiang et al, 2022 ) make this more complicated than we had anticipated. When I give talks about this work, different people have different reactions, some of them asking “Why are you making things so complicated?” [both laugh].…”