Agouti^{VariableYellow}

Mice with the A^VY Agouti allele have a gene oscillation mechanism that works only some of the time, producing variable phenotype. Some of the mice are yellow, and some are brown, but most have a mottled appearance. The gene adopts different settings in individual mice. The allele contains a nearby transposable element (IAP), which has its own promoter that overrides the normal oscillating promoter of Agouti. The epigenetic state of IAP can determine the level of expression of pigment. If the promoter is continuously on, it produces more yellow pigment. Methylation state of A^VY can be altered by diet. Feeding pregnant A^VY/a mice (crossed with an a/a father) folic acid and vitamin B12 supplements, there is an increase in methyl donors, and increased proportion of methylated (off) A^VY alleles. This reduces the frequency of yellow phenotypes in offspring. There is no effect when fathers are fed a supplemented diet. The promoter responds to light cycles.

Senescence is an endogenous trigger for microRNA-directed transcriptional gene silencing in human cells

Transcriptional repression of proliferation-promoting genes are regulated by retinoblastoma (RB1) and E2F repressor complex. AGO2, RB1, and miRNAs physically and functionally interact to repress RB1/E2F-target genes in senescence-associated transcriptional gene silencing (SA-TGS).

It should be changed to emphasize that many RNAs are not translated into proteins. Many gene products are non-coding RNAs, and oftentimes RNA can be reverse-transcribed into DNA. It was created in the 1960s.

DNA ↔ RNA → Protein

The noncoding RNA revolution-trashing old rules to forge new ones

Describes the pathway of ncRNA research, where every "rule" seems to be overturned.

Clark Kent

A H3K9 methyltransferase. Binds to repeats, and methylates for heterochromatin spread. Required for telomeric heterochromatin assembly in S. pombe, but is independent of RNAi. Complementary to Superman, which it suppresses. Works in other processes.

Transgenerational inheritance of paternal traumatic exposure: aversion behaviour in conditioned mice

Conditioned F0 male mice with acetophene and propanol gases. After 13 days, mated the mice with naïve females, and separated them from the females 10 days later. Recorded the association time/aversion index of F1 males towards acetophene and propanol odours. F1 mice detected the smells at lower concentrations if their father was exposed to the same smell. Effects correlated with altered DNA methylation in the Olfr loci in the sperm of conditioned mice. An argument against social transmission. Effects were transmitted to grandchildren.

An abundant class of non-coding DNA can prevent stochastic gene silencing in the C. elegans germline

Investigated the varying states of expression throughout the genome of C. elegans by inserting transgenes throughout with an emphasis on germ cells, known to exhibit tight control on gene expression. Found that transgenes were more likely to be expressed in regions rich in a class of non-coding DNA elements containing repetitive adenines or thymines (PATCs). Put forth an alternative element contained within the DNA itself that may function to control expression of genes.

Transgenerational epigenetic inheritance: myths and mechanisms

Found that epigenetic inheritance depends on epigenetic state at conception, and during pregnancy.

Widespread RNA binding by chromatin-associated proteins

Prior to this study, it was known that RNA could interact with CAPs to regulate their localization activity. Whether the interaction was a general mechanism or limited to a few specific RNA interactions is unknown. Employed techniques to determine widespread RNA-CAP interaction. Determining RNA regulation of Cap would help answer questions about how chromatin state is regulated, and where and when specific chromatin modifiers are established. A powerful resource, furthering our understanding of the role of RNA in epigenetic regulation. Produced reproducible and statistically significant data regarding RNA targets for 24 CAPs and RBPs. Binding of proteins were discovered using fRIP-Seq. Suggests that certain proteins have stronger preference for transcripts with more exons. Silencing proteins may require more spliced RNA to modulate activity. Previous studies focus on lnc-RNA-CAP interactions. Found that mRNA associates more with CAPs than lncRNA. Suggests that mRNA might play a role in acting as a guide for chromatin modifying complexes. This paper created more questions, showing us what we do not know.

Transgenerational transmission of environmental information in C. elegans

Report observations that a temperature-induced change in expression from Caenorhabditis elegans heterochromatic gene array can endure for at least 14 generations. Inheritance is primarily in cis with the locus, occurring through both oocytes and sperm, associated with altered methylation of H3K9Me3, before onset of zygotic transcription. Expression profiling revealed that temperature-induced expression from endogenous repressed repeats can be inherited for multiple generations. Long-lasting epigenetic memory of environmental change is possible in C. elegans. The worms contained cloned repressed mCherry arrays of genes. The worms were grown at 25ºC, and then for 15 generations grown at 20ºC. The de-repression of mCherry persisted for 15 generations. The most generations of transgenerational inheritance ever observed. In addition to causing genetic change, impaired DNA replication during embryonic development can have major epigenetic consequences for the genome. Identified impaired DNA replication as the cause of increased expression from a repressed transgene. The acquired expression state behaved as an "epiallele", inherited for multiple generations before fully resetting. Depression was not restricted to the transgene; caused by a global reduction in heterochromatin-associated histone modifications due to impaired retention of modified histonse on DNA during replication in the early embryo. Impaired DNA replication during development globally depresses chromatin, creating a new intergenerationally inherited epigenetic expression state. Looked at transcription start sites (TSS) of three genes. There are gaps in the TSS of genes, where marks are absent. The worms with knockout genes of replication factors were mated to mCherry array worms. The replication deficiency lasted only during embryonal developmpent. Impaired DNA replication de-repressed the mCherry array, globally altered histone modifications, and interfered with inheritance of H3K72Me3-modified paternal histones.

Full-length autonomous transposable elements are preferentially targeted by expression-dependent forms of RNA-directed DNA methylation

Reactivated TEs harm the host via intergenomic mobilization, causing genome instability. Discovered a new mechanism of RdDM, and the diversity and specificity of these pathways. Determined that the length and structure of the TE determines which RdDM pathway the cell uses to silence it. Used ddm1 Arapidopsis. The mutant experienced genome-wide methylation loss and global TE reactivation, leaving the cell in a perpetual state of re-silencing. Found that RDR6-RdDM pathway which works towards re-establishing the silencing of the TE by directing DNA methyltransferases to the locus.

Argonaute-containing RNA-induced silencing complex

Binds to siRNAs and unwinds them, then is guided by the single stranded siRNAs to cleave target mRNA. Converts dsRNA to ssRNA, and amplifies the RNAi response. Presents anti-sense ssRNA to a new molecule of target sense RNA. Conserved in many species.

A potent mechanism for repression of gene expression. Works at the repression of translation, and by interfering with the stability of target mRNA. Participates in the formation of heterochromatin at the site of transcription. A "molecular mop". Cells actively destroy dsRNA. Suppresses retroviruses and transposons. An ancient and conserved phenomenon. Results in degradation of the target mRNA. Includes PTGS. A defence mechanism against dsRNA and retrovirues.

1. dsRNA is cleaved into double-stranded siRNA fragments by DICER.

2. siRNAs bind to RISC, forming an inactive complex.

3. The dsRNA unwinds into ssRNA by its helicase activity, forming an active RISC complex.

4. RISC is guided by the single-stranded siRNA to cleave target mRNA, with SLICER activity via ARGONAUTE.

Tertiary siRNAs mediate paramutation in C. elegans

Heritable epigenetic silencing of both endogenous RNA and exogenous RNA is RNAi dependent, and can be maintained over many generations in the absence of an initial trigger.

Fission yeast

It can be used to make the African beer called pombe. It is very different from S. cerevisiae, about as equally as related to it as it is to H. sapiens. Has four chromsomes, and more complicated chromatin structure than S. cerevisiae. Has otrR and otrL repeats about its centromeres. There is bi-directional transcription at otr repeats, and these transcripts accumulate in DCR, RdRP, and AGO mutants. siRNA silences the chromatin. Its HP1 is SWI5. It has DNA methylation and transcriptional RNA silencing.

Disruption of histone methylation in developing sperm impairs offspring health transgenerationally

The lifetime experiences of the father can be transmitted to offspring, affecting health and development. Underlying mechanisms are unclear. Unlike in somatic cells, there are few nucleosomes in sperm cells, and function in epigenetic inheritance is unknown. Show that epigenetic inheritance of aberrant development can be initiated by histone demethylase activity in developing sperm, without changes to DNA methylation at CpG-rich regions.

Epigenetic (re)programming of caste-specific behaviour in the ant Camponotus floridanus

Molecular mechanisms behind social behaviour has been studied in solitary species such as fruit flies, but eusocial insects present a way to study complex social interactions. Acetylation of histone residues has been proposed as a way that insect colonies regulate division of labour, in particular H3K27Ac has been associated with production of distinct behaviorual classes, such as queen honeybees. Showed that epigenetic factors play a large role in the division of labour in C. floridanus, and that these behaviours can be modified pharmacologically.

Germline-inherited H3K27Me3 restricts enhancer function during maternal-to-zygotic transition

Determined the origins of H3K27Me3, and how it is distributed throughout early development, and what effect maternally inherited E(z) has on the epigenetic silencing of genes. Intergenerational inheritance of epigenetic marks is crucial to embryonic development. Used Drosophila melanogaster as a model organism, providing insight into the mechanism of inheritance and epigenetic imprinting in eukaryotes. Experiments were not very clean, using a temperature-sensitive allele for E(z).