Epigenetics Flashcards

Epigenetics

27.1 Introduction

• Epigenetic effects arise from nucleic acid modification post-synthesis or perpetuation of protein structures.

• Replication of a methylated site leads to hemimethylated DNA, with methylation only on the parental strand.

• Heterochromatin and Euchromatin are different states of chromatin.

• Heterochromatin is created by proteins associated with histones.

• Prion: A proteinaceous infectious agent behaving as an inheritable trait without nucleic acid.

  • Examples: PrPSc (scrapie in sheep, bovine spongiform encephalopathy), PSI (inherited state in yeast).

27.2 Heterochromatin Propagation

• Heterochromatin nucleates at specific sequences, propagating along the chromatin fiber.

• Nucleation results from proteins binding to specific sequences.

• Genes within heterochromatin regions are inactivated.

• The inactive region's length varies, causing position effect variegation (PEV).

• Gene expression states (on/off) influence phenotype based on variable positions.

• Similar effects occur at telomeres (telomeric silencing) and silent cassettes in yeast mating type loci.

27.3 Heterochromatin and Histones

• HP1: Key protein in mammalian heterochromatin, binding to methylated histone H3, forming higher-order chromatin structures.

• HP1 contains a chromodomain and a chromoshadow domain.

• Methylation of histone H3 creates a binding site for HP1.

• Rap1 initiates heterochromatin formation in yeast by binding to specific DNA sequences.

• Rap1 targets include telomeric repeats and silencers at HML and HMR.

• Rap1 recruits Sir3 and Sir4, interacting with H3 and H4 N-terminal tails.

• Sir2 deacetylates H3 and H4 N-terminal tails, promoting Sir3 and Sir4 spreading.

• RNAi pathways promote heterochromatin formation at centromeres.

27.4 Polycomb and Trithorax

• Polycomb group proteins (Pc-G) perpetuate a state of repression through cell divisions.

• Pc-G proteins maintain repression.

• Polycomb response element (PRE): DNA sequence required for Pc-G action.

• PRE is a nucleation center for Pc-G proteins to propagate an inactive structure, forming an epigenetic memory.

• Trithorax group proteins (TrxG) antagonize Pc-G actions.

• Pc-G and TrxG can bind to the same PRE with opposing effects.

27.5 CpG Islands and Methylation

• Most DNA methyl groups are on cytosine in CpG doublets.

• Replication converts fully methylated sites to hemimethylated sites.

• DNA methyltransferase: Enzyme adding a methyl group to specific DNA target sequence.

• Demethylase: Enzyme removes a methyl group from DNA, RNA, or protein.

• De novo methyltransferase: Enzyme adding a methyl group to an unmethylated DNA target sequence.

• Hemimethylated sites are converted to fully methylated sites by a maintenance methyltransferase.

• TET proteins convert 5-methylcytosine to 5-hydroxymethylcytosine, leading to DNA demethylation.

27.6 Epigenetic Inheritance

• Epigenetic effects arise from nucleic acid modification post-synthesis or perpetuation of protein structures without changing the DNA sequence.

• Epigenetic effects may be inherited through generations (transgenerational epigenetics).

• Aberrant epigenetic inheritance may be preventable.

• Acetylated histones are conserved and randomly distributed to daughter chromatin fibers at replication.

27.7 Yeast Prions

• Sup35 protein in wild-type soluble form is a termination factor for translation.

• Sup35 can exist in an alternative oligomeric aggregate form, inactive in protein synthesis.

• Oligomeric form presence causes newly synthesized protein to acquire the inactive structure.

• Amyloid fibers: Insoluble fibrous protein polymers with a cross β-sheet structure, generated by prions or dysfunctional protein aggregations (e.g., Alzheimer's).

• Conversion between the two forms is influenced by chaperones.

• Wild-type form has the recessive genetic state psi–, and the mutant form has the dominant genetic state PSI+.

28.1 Introduction

• Many biological processes, including X chromosome inactivation and genomic imprinting, are mediated through epigenetic mechanisms, e.g., DNA methylation.

28.2 X Chromosomes

• Dosage compensation: Mechanisms compensating for the discrepancy between two X chromosomes in one sex and one in the other.

• X-linked variegation is caused by the random inactivation of one X chromosome in each precursor cell.

• Constitutive heterochromatin: Inert state of permanently nonexpressed sequences (e.g., satellite DNA).

• Facultative heterochromatin: Inert state of sequences that also exist in active copies (e.g., one mammalian X chromosome in females).

• One of the two X chromosomes is inactivated at random in each cell during embryogenesis of eutherian mammals.

• Single X hypothesis: Theory describing the inactivation of one X chromosome in female mammals.

• In cases with more than two X chromosomes, all but one are inactivated (the n–1 rule).

• X inactivation center (Xic): Cis-acting region on the X chromosome necessary to ensure only one X chromosome remains active.

• Xic includes the Xist gene, coding for an RNA found only on inactive X chromosomes.

• Xist recruits Polycomb complexes, which modify histones on the inactive X chromosome.

• The mechanism preventing Xist RNA accumulation on the active chromosome is unknown.

28.3 Chromosome Condensation

• SMC (structural maintenance of chromosome) proteins are ATPases including condensins and cohesins.

• A heterodimer of SMC proteins associates with other subunits.

• Condensins cause chromatin to be more tightly coiled by introducing positive supercoils into DNA.

• Condensins are responsible for condensing chromosomes at mitosis.

• Chromosome-specific condensins condense inactive X chromosomes in C. elegans.

28.4 DNA Methylation and Imprinting

• Paternal and maternal alleles may have different methylation patterns at fertilization.

• Methylation is usually associated with inactivation of the gene.

• When genes are differentially imprinted, embryo survival depends on whether a functional allele is provided by the parent with the unmethylated allele.

• Survival of heterozygotes for imprinted genes differs depending on the cross direction.

• Imprinted genes occur in clusters and depend on a local control site where de novo methylation occurs unless specifically prevented.

28.5 Imprinted Genes

• Imprinted genes are controlled by methylation of cis-acting sites.

• Methylation may be responsible for either inactivating or activating a gene.

• The ICR is methylated on the paternal allele, where Igf2 is active and H19 is inactive.

28.6 Prions and Diseases

• kuru: A human neurological disease caused by prions.

• The protein responsible for scrapie exists in two forms: wild-type noninfectious PrPC (susceptible to proteases) and disease-causing PrPSc (resistant to proteases).

• The neurological disease can be transmitted to mice by injecting the purified PrPSc protein.

• The recipient mouse must have a copy of the PrP gene coding for the mouse protein.

• The PrPSc protein can only infect an animal with the same type of endogenous PrPC protein.

• The PrPSc protein perpetuates itself by causing newly synthesized PrP protein to take up the PrPSc form instead of the PrPC form.

• Multiple strains of PrPSc may have different conformations of the protein.

• epialleles are variants of the same gene that have different epigenetic modifications, leading to distinct phenotypic expressions.

  • obligate

  • facilitative

  • pure