Week 3 Textbook

Epigenetic Inheritance

A form of inheritance superimposed on genetic (DNA-based) inheritance. It is based on inherited chromatin structure and chemical modifications (like DNA methylation) that can be passed from a cell to its descendants.

Heterochromatin

A highly condensed form of chromatin visible in interphase nuclei. It is transcriptionally repressive, restricts gene expression, and is concentrated at centromeres, telomeres, and other variable locations.

Euchromatin

The less condensed form of chromatin that makes up the majority of the genome during interphase. It is more accessible for transcription.

Position Effect

A phenomenon where a normally euchromatic gene is silenced after being translocated near heterochromatin. This demonstrates the spreading and self-propagating nature of the heterochromatic state.

Core Histone Modifications

Covalent, reversible modifications to the amino acid side chains of histones (H2A, H2B, H3, H4), including acetylation, methylation, and phosphorylation. They occur on the unstructured N-terminal tails and the globular core.

Histone Acetylation

The addition of an acetyl group to a lysine residue. It removes the positive charge, loosening chromatin structure, and serves as a mark for other proteins to bind. It competes with lysine methylation.

Histone Methylation

The addition of one (mono-), two (di-), or three (tri-) methyl groups to a lysine or arginine residue. The effect depends on the specific residue and degree of methylation (e.g., H3K9me3 recruits HP1 for heterochromatin).

Histone Phosphorylation

The addition of a phosphate group to a serine, threonine, or other residue. It adds a negative charge and can signal DNA damage or other processes.

Writer Enzymes

Enzymes that add covalent modifications to histones (e.g., Histone Acetyltransferases - HATs, Histone Methyltransferases - HMTs).

Eraser Enzymes

Enzymes that remove covalent modifications from histones (e.g., Histone Deacetylases - HDACs, Histone Demethylases).

Reader Proteins

Proteins that contain domains (e.g., bromodomains, PHD domains) that recognize and bind to specific histone modifications (e.g., ING PHD domain binds H3K4me3).

Reader Complex

A large protein complex containing multiple reader modules. It binds tightly only to a specific combination of histone marks and recruits other proteins to execute a biological function (e.g., gene activation or silencing).

Histone Code Hypothesis

The idea that specific combinations of histone modifications have specific meanings for the cell, determining how the DNA in that chromatin is accessed (e.g., for replication, repair, or gene expression).

Reader-Writer Complex

A protein complex containing both reader and writer enzymes. It can spread a chromatin mark along a chromosome: the reader binds the mark, activating the writer to modify the adjacent nucleosome, creating a chain reaction.

Histone Variants

Non-standard versions of core histones (e.g., H3.3, CENP-A, H2A.X, H2A.Z) that are incorporated into nucleosomes in a site-specific manner throughout the interphase to confer specialized functions.

Function of Histone Variants

They confer specialized functions: H3.3 (transcriptional activation), CENP-A (centromere function), H2A.X (DNA repair), H2A.Z (gene expression, chromosome segregation), macroH2A (transcriptional repression, X-inactivation).

Mechanism of Variant Incorporation

ATP-dependent chromatin remodeling complexes, in concert with histone chaperones, catalyze the exchange of standard histones for variants at specific sites on chromosomes.

Transcription Activators

Proteins that bind to specific DNA sequences (enhancers/promoters) and increase transcription initiation by recruiting the transcriptional machinery and altering local chromatin structure.

Coactivators

Protein complexes recruited by transcription activators that perform the biochemical tasks of transcription initiation. They do not bind DNA directly. Examples include the Mediator complex and complexes containing HATs.

Mediator Complex

A large coactivator complex (~30 subunits) that serves as a bridge between DNA-bound transcription activators, RNA polymerase II, and the general transcription factors to facilitate assembly at the promoter.

Ways Activators Alter Chromatin

1. Recruit histone-modifying enzymes (e.g., HATs). 2. Recruit ATP-dependent chromatin remodeling complexes. 3. Recruit histone chaperones for nucleosome removal or histone replacement.

Order of Histone Modifications (Interferon Example)

1. Activator recruits HAT → Acetylates H3K9 & H4K8. 2. Activator recruits kinase → Phosphorylates H3S10 (only after K9 acetylation). 3. H3S10ph signals HAT → Acetylates H3K14. 4. TFIID & remodeling complex bind via bromodomains.

Transcription Pausing

A common step where RNA polymerase II halts after transcribing ~50 nucleotides. Further elongation requires a transcription activator bound downstream to release it, providing a mechanism for rapid response.

Transcriptional Synergy

The effect of multiple transcription factors working together is multiplicative (the product of their individual effects), not additive. This allows for very precise control over gene expression levels.

DNA Methylation (Vertebrates)

The covalent addition of a methyl group to the 5' carbon of cytosine bases, primarily in the sequence CG. It is a mechanism for stable, heritable gene repression.

Maintenance Methyltransferase

An enzyme that maintains DNA methylation patterns after replication. It recognizes hemi-methylated DNA (methylated on the parent strand) and methylates the cytosine on the daughter strand.

De Novo Methyltransferases

Enzymes that establish new DNA methylation patterns during development, directed by sequence-specific DNA-binding proteins.

Effects of DNA Methylation on Transcription

1. Methyl groups in the major groove directly block transcription factor binding. 2. Recruits methyl-CG-binding proteins, which recruit histone modifiers to establish repressive chromatin.

CG Islands

Regions of the genome (~1000 bp) with a high density of unmethylated CG sequences. They are associated with ~60% of human gene promoters, including virtually all housekeeping genes.

Why CG Islands Exist

They remained unmethylated in the germ line, protecting them from accelerated mutation via deamination of 5-methylcytosine to thymine, which eliminated CGs in the rest of the genome.

Genomic Imprinting

An epigenetic phenomenon where the expression of a gene depends on its parental origin (either the maternally or paternally inherited copy is silenced). About 300 genes are imprinted in humans.

Imprinting Mechanism

Uses DNA methylation as a mark to distinguish parental alleles. This mark is established in the germ line, protected from post-fertilization demethylation, and somatically inherited via maintenance methyltransferases.

Igf2 Imprinting Example

On the paternal chromosome: methylation of an insulator blocks CTCF binding, allowing enhancers to activate Igf2. On the maternal chromosome: the unmethylated insulator binds CTCF and blocks Igf2 expression.

Kcnq1 Imprinting Example

On the paternal chromosome: the unmethylated allele transcribes a long noncoding RNA (lncRNA) that remains tethered and recruits repressive chromatin modifiers, silencing the gene. On the maternal chromosome: methylation silences the lncRNA promoter, allowing Kcnq1 expression.

Long Noncoding RNA (lncRNA)

An RNA molecule over 200 nucleotides long that does not code for a protein. In imprinting (e.g., Kcnq1), it can act as a scaffold to recruit repressive chromatin-modifying complexes.

X-Chromosome Inactivation

A striking example of chromosome-wide, heritable alteration in chromatin structure that modulates gene expression to achieve dosage compensation in females.

Cell Memory

The stable, heritable maintenance of gene expression patterns through cell divisions, achieved through positive feedback loops and epigenetic mechanisms like DNA methylation and histone modification inheritance.

Bromodomain

A protein domain found in reader proteins (e.g., within TFIID and chromatin remodeling complexes) that specifically recognizes and binds to acetylated lysine residues on histones.

PHD Domain

A protein domain found in reader proteins (e.g., the ING protein in the NURF complex) that specifically recognizes and binds to methylated lysine residues on histones (e.g., H3K4me3).

Cooperative Binding

A positive interaction where the binding of one transcription factor to DNA facilitates the binding of a neighboring factor.

Chromatin Remodeling Complexes

Multi-subunit complexes that use ATP hydrolysis to slide, evict, or restructure nucleosomes, making DNA more or less accessible. They are recruited by transcription regulators.

Histone Chaperones

Proteins that escort histones (both standard and variants) and facilitate their deposition onto DNA or their exchange in nucleosomes, often in concert with remodeling complexes.

Insulator Element

A DNA sequence that can block the interaction between an enhancer and a promoter. Its function can be regulated by methylation (e.g., in Igf2 imprinting, methylation inactivates the insulator).

CTCF

A key protein that binds to insulator elements and helps form chromatin loops. Its binding can be blocked by DNA methylation, as seen in the Igf2 imprinting mechanism.

Angelmann Syndrome

A human neurological disorder that exemplifies the effect of imprinting; it results from a deletion of a gene on one chromosome and the silencing of the intact copy on the other homolog due to imprinting.