epigenetic inheritance

positive feedback of polycomb protein complexes

• structure of complexes means that histone modification by one leads to recruitment of other

• can lead to repeated modification-binding cycles

• could account for spreading of complexes on chromatin

• important part of models of inheritance through cell division

reader and modifier domains in protein complexes

• PRC2: both introduces and binds to K27me

• SUVAR39: both introduces and binds to K9me

• occurs through distinct domains in protein complexes

• single protein complex can potentially serve as positive feedback to spread heterochromatin

histones during DNA replication

daughter strands of DNA generated carry combination of old and new nucleosomes (recycled or nascent histone proteins)

histone modification copy mechanism during DNA replication

• copying occurs from previously methylated to unmethylated histones

• old histones have to be re-deposited locally

• interaction between old histones and components of replication machinery ensure this

PRC2-dinucleosome structure

• composed of one monomer that is unmodified and one monomer that already has H3K27me3

• EED subunit is bound to H3K27me3 nucleosome

• EZH2 (methyltransferase) is bound to substrate nucleosome

• binding of EED to H3K27me3 activates enzymatic activity of the complex

• strong evidence for histone copying mechanism during DNA replication

intergenerational epigenetic inheritance

due to initial, direct exposure of gametes to stimulus in F0

transgenerational epigenetic inheritance

due to transmission of epigenetic change to gametes independently of initial exposure (gametes were never exposed to stimulus)

evidence for transgenerational epigenetic inheritance model systems

• corn: transposon insertion in colour gene promoters

  • variable DNA methylation in transposon leads to variegated expression

  • stable for generations

• mice: methylation state of the IAP (transposon-derived) in Agouti promoter can be maintained through germline development

• epigenetic transmission via DNA methylation rare in mammals because of epigenetic reprogramming in germline

  • more common in plants because germ cells arise from somatic cells (reprogramming is incomplete)

• transposons may be relatively resistant to reprogramming → may be key drivers of transgenerational effects

non-gametic epigenetic inheritance in mice

• low maternal care (licking and grooming) leads to CpG methylation in promoter of gene for glucocorticoid receptor in the hippocampus of the pups

• → blocks transcription factor binding → lowers expression → activation of hormonal stress response

• stress response sustained into adulthood, female adults transmit it to their pups

• example of temporal stability of gene expression state

• maternal care phenotype passed on through generations but no evidence that this involves germline transmission

intergenerational epigenetic inheritance of effects of environmental exposure in humans

• Dutch famine (1944)

• male babies born to mothers who lived through the famine were small

• same effect noted in children born after famine was over

inter- and transgenerational inheritance of effects of environmental exposure

• evidence that changes in paternal diet/metabolism can affect sperm → affect health of offspring

  • industrial chemicals, metals, and abuse of drugs being studied

• likely not by mechanism of DNA methylation or histone modifications

small interfering RNAs (siRNAs)

• 22-24 nucleotides long

• play roles in post-transcriptional gene silencing

piRNAs

• germline-specific version of siRNA

• involved in silencing transposons in germline

small RNAs and epigenetics

• small RNAs regulate gene expression at transcriptional and post-transcriptional levels

• are transmissible between cells

• siRNAs don’t affect transcription in mammals

• piRNAs only known to act on highly repetitive sequences (transposons)

• other types of non-coding RNAs could play analogous roles at endogenous genes under some circumstances

  • tRNA-derived small RNAs (tsRNAs)