As we have often discussed in GEITP emails, epigenetics represents “effects beyond DNA sequence (nucleotide changes) that result in an impact on phenotype.” It appears that most, if not all DNA-mutation-caused traits are also affected/modified to some degree by epigenetics (environmental adversity and even transgenerational effects). Each cell type in our body is likely to have its own unique epigenome. The more than 200 epigenomes in human can be altered by DNA methylation, RNA-interference, histone modifications, and chromatin remodeling.
Some epigenetic variants can be inherited by a parent’s offspring (or the offspring’s offspring) –– indicating the likelihood of a mechanism for biological heredity not based on DNA sequence. For example, cigarette smoking during pregnancy by a grandmother appears to increase risk of asthma in the granddaughter. Famine at the time a male is entering puberty sends an unknown transgenerational message to his grandson, resulting in a 4-fold less risk of type-2 diabetes; famine in the same (Swedish farming) population, at the time a female’s oocytes are forming in utero, increases the risk of obesity and diabetes 4-fold in that baby’s granddaughter. Exposure of the endocrine disruptor vinclozolin (anti-androgenic compound) or methoxychlor (estrogenic compound) to a pregnant rat during gonadal sex development in utero produces an adult phenotype –– in the F1 to F4 generations –– of decreased spermatogenesis and greater risk male infertility. Drug tolerance (to the anesthetic, benzyl alcohol) in the fly has been shown to be caused by epigenetic histone modification and transcriptional induction of slo, an ion-channel gene.
In the attached editorial and two full papers (one using the flatworm Caenorhabditis elegans, the other the fly Drosophila melanogaster) show that epigenetic states can be transmitted by chromatin mechanisms for many generations –– possibly indefinitely. Authors used C. elegans carrying a transgene driven by the heat-shock protein Hsp90 promoter to compare effects of growth at 25 °C and 20 °C. At 25 °C, the promoter showed considerable activity that was retained in progeny raised at 20 °C. This effect was much stronger when the transgene was present in extrachromosomal multicopy arrays: growth at 25 °C for a single generation resulted in increased expression for the next seven generations raised at 20 °C. Authors found that: this “memory” could be transmitted via both eggs and sperm; was inherited with the genome, not through the cytoplasm; did not depend on small RNAs; and was associated with loss of methylation at lysine-9 of histone H3 (H3K9) in the transgene. In fact, repression of the transgene at 20 °C required the SET-25 histone methyltransferase responsible for H3K9 trimethylation in the embryo.
In the other paper, authors started with flies carrying a transgenic construct in which the white gene (required for red eye pigmentation) was accompanied by Fab-7, one of the regulatory elements of the Drosophila Bithorax complex –– consisting of a Polycomb response element (PRE) and a chromatin insulator. It was found that PRE could recruit Polycomb complexes PRC1 and PRC2 and repress the white gene, resulting in eyes containing varying proportions of white- and red-pigmented cells. After using fly genetics to produce a state of ‘increased epigenetic plasticity’, authors selected progeny in which the white transgene was either less repressed (eyes with more red cells) or more strongly repressed (eyes with more white cells). They then bred the more repressed or the less repressed flies –– selecting more extreme phenotypes in each subsequent generation.
After a few generations, the extreme phenotype (entirely white or entirely red eyes) became stable and was transmitted to the progeny. Authors therefore established stable “epi-lines” (which contain no relevant changes in DNA sequence). Furthermore, epi-alleles had the remarkable property of converting ‘naive’ alleles of the transgene into the same epi-allelic state, an effect that is highly reminiscent of the well-known “para-mutation phenomenon” in maize.
In a population of flies containing the same Fab-7-white transgene, repression was variable from one individual to another, but these variations were not normally transmitted to the progeny. This is not surprising: PREs are set in their ways in specific cells and specific tissues. Little is known about the state of Polycomb repression in the germ line, but, in the embryo, Polycomb target genes must be again activated or repressed according to developmental and tissue-specific cues, not the state of repression in the parents. But is this entirely true?
These findings raise more questions than answers. How is the clustered configuration recreated in the germ line of every generation –– when genome architecture is dismantled every cell cycle, and is absent in the early embryo? Any causative chromatin configuration would have to be reconstructed on the basis of epigenetic modifications.
If the closely associated state is so stably inherited, why has it not prevailed as the natural condition of Fab-7 and similar elements? Perhaps it has. Normally, flies do not carry transgenes containing additional Fab-7 elements nor is there selection for extreme phenotypes.
How common is this kind of epigenetic inheritance, and how frequently has it gone undetected? Could mutations in humans cause similar plastic states leading to transgenerational epigenetic inheritance involving gene-drug response and gene environmental toxicant response? A lot of research remains to be done, but the doors to a world of Lamarckian inheritance are flung wide open. Inheritance of longer necks in giraffes, as a mechanism of successful survival, has most likely occurred because of transgeneratinal epigenomic changes.
Nat Genet June 2o17; 49: 821–823 [News’N’Views) + 49: 876–886 + Science 2o17; 356: 320–323 [whole articles]