Source: Chapters 8–9, University of Central Florida
Tags: nucleosome, histone, histone code, H2A, H2B, H3, H4, H1, acetylation, methylation, chromodomain, bromodomain, HAT, HDAC, 30 nm fibre, solenoid, zigzag, euchromatin, heterochromatin, epigenetics, DNA methylation, PCNA, nucleosome positioning, semiconservative histone inheritance, p53, cell cycle regulation, cancer
Difficulty: Intermediate to Advanced Prerequisites: Parts 1 and 2 of this set (genome organisation and cell cycle), basic protein chemistry (amino acids, protein domains).
This section covers how DNA is wrapped around histone proteins to form nucleosomes, how nucleosomes assemble into higher-order chromatin structures, and how chemical modifications to histones and DNA regulate gene expression without changing the DNA sequence (epigenetics). This is where molecular biology meets gene regulation: the same genome can produce vastly different cell types depending on which regions are open or closed. Understanding the histone code, nucleosome remodelling, and how epigenetic marks are inherited is essential for connecting genome structure to function.
DNA wraps around histone octamers to form nucleosomes (the 10 nm fibre), which can compact further into 30 nm fibres regulated by linker histone H1. Histone tail modifications, principally acetylation (activating) and methylation (often silencing), form a "histone code" read by proteins with bromodomains or chromodomains. These epigenetic marks influence transcription and can be passed to daughter cells during replication, with implications for development and cancer.
Nucleosome
The fundamental unit of chromatin: ~147 bp of DNA wrapped 1.65 times around a histone octamer. The nucleosome is not sequence-specific; it interacts with the minor groove of DNA via non-specific interactions.
Histone octamer
The protein core of the nucleosome, consisting of two copies each of H2A, H2B, H3, and H4. H1 is the linker histone and is not part of the octamer core.
H3 and H4
Found as a tetramer (H3-H4)₂ in the nucleosome. H3-H4 tetramers form first during nucleosome assembly.
H2A and H2B
Found as dimers (H2A-H2B) in the nucleosome. Two dimers join the H3-H4 tetramer to complete the octamer.
H1 (linker histone)
Not part of the core octamer. H1 binds to linker DNA between nucleosomes and regulates higher-order chromatin structure (the 30 nm fibre). H1 is not found as a dimer or tetramer in the nucleosome.
Histone tails
The N-terminal extensions of histone proteins that project outward from the nucleosome. The amino acids on these tails (mostly lysines and arginines) interact with DNA and are the targets for post-translational modifications.
Histone code
The combination of different modifications on the histone N-termini (tails) that can be read by proteins with chromo or bromodomains, influencing gene expression. This is not about modifications on the histone fold domain, nor about DNA base modifications.
Acetylation
The addition of an acetyl group to lysine residues on histone tails, carried out by histone acetyltransferases (HATs). Acetylation generally leads to transcriptional activation by reducing the positive charge of histones, weakening histone-DNA interactions.
Methylation (of histones)
The addition of methyl groups to histone tail residues. Methylation of histone tails is generally associated with transcriptional silencing (though some methylation marks are activating, depending on context).
HAT (histone acetyltransferase)
An enzyme that adds acetyl groups to histone tails, decreasing histone-DNA interactions and activating gene transcription. HATs do not add lysines to histones; they modify existing lysines.
Bromodomain
A protein domain that recognises and binds acetylated lysines on histone tails. Involved in nucleosome remodelling and transcriptional activation.
Chromodomain
A protein domain that recognises and binds methylated lysines on histone tails. Associated with heterochromatin formation and transcriptional silencing.
30 nm fibre
A higher-order chromatin structure formed when nucleosomes (10 nm fibre) compact further. Two models exist: the solenoid model and the zigzag (two-start) model. Regulated by H1.
Zigzag (two-start) model
The predominant higher-order chromatin structure observed in eukaryotes, where alternating nucleosomes from two stacks interleave.
Solenoid model
A model for the 30 nm fibre in which nucleosomes stack consecutively in a helical arrangement along a single axis.
Heterochromatin
Tightly packed, transcriptionally silent chromatin. Associated with methylated histones and chromodomains.
Euchromatin
Loosely packed, transcriptionally active chromatin. Associated with acetylated histones and the 10 nm fibre.
PCNA (proliferating cell nuclear antigen)
A sliding clamp protein that, among other functions, helps guide histones onto newly synthesised DNA during replication.
DNA methylation
The addition of methyl groups to cytosine bases in DNA (typically at CpG sites). Generally associated with gene silencing. Plays a role in cancer formation.
Epigenetics
Heritable changes in gene expression that do not involve changes to the DNA sequence itself. Includes histone modifications, DNA methylation, and non-coding RNA regulation.
DNA wraps around the nucleosome 1.65 times (not 1.47, not 2, not 1)
The nucleosome interacts with the minor groove of DNA via non-specific interactions
The nucleosome is not sequence-specific, but its positioning is influenced by:
The location of other DNA-bound proteins
The alternation of A/T-rich and G/C-rich sequences in the DNA
PCNA (which helps guide histones onto newly synthesised DNA)
DNA in the nucleosome has a linking number change of -1.2, but wrapping alone predicts -1.65
The discrepancy is because DNA in the nucleosome has more base pairs per turn than standard B-form DNA, which partially compensates for the negative writhe introduced by wrapping
The amino acids projecting outward from histones that interact with DNA are mostly lysines and arginines (positively charged, basic amino acids)
These interact with the negatively charged DNA backbone
The four core histone proteins are H2A, H2B, H3, and H4 (two copies each per nucleosome)
H1 is NOT a core histone; it is the linker histone
A common false statement: "The four core histones are H1, H2A, H2B, and H3." This is wrong because H1 is not a core histone, and H4 is missing.
DNA wraps around the octamer in a left-handed manner, inducing negative supercoils
The 30 nm fibre is regulated by H1
The zigzag (two-start) model is the predominantly observed higher-order structure in eukaryotes
The solenoid model shows nucleosomes stacking along a single axis
You would expect low levels of transcription in the solenoid fibre, methylated DNA, heterochromatin, and metaphase chromosomes
The exception (where transcription does occur) is the 10 nm fibre
The 10 nm fibre represents euchromatin, accessible to transcription machinery
Acetylation of histone tails generally leads to transcription (activation)
Methylation of histone tails generally leads to silencing
HATs decrease histone-DNA interactions by acetylating lysines, which activates transcription
HATs do not add lysines to the N-terminus, do not use ATP to slide DNA, and do not methylate
Bromodomains recognise acetylated lysines (associated with active chromatin)
Chromodomains recognise methylated lysines (associated with heterochromatin/silencing)
Bromodomains are involved in nucleosome remodelling
In the semiconservative model: histones remain associated with the DNA and are randomly distributed (~50/50) among the two daughter strands
In the asymmetric model: one daughter DNA molecule gets 100% of the old histones; the other gets entirely new histones
PCNA helps guide histones onto newly synthesised DNA
Possible mechanisms include: inherent markers in DNA sequences, nucleosomes recruiting modification enzymes to adjacent nucleosomes, and bridge proteins spanning both sides of the replication fork
Bromodomains "remembering" old modifications and transferring them is NOT a currently accepted explanation
During differentiation from blastocyst to a specific cell type, cells are remodified (epigenetic marks are reset and re-established)
Protamines replace histones in sperm (not eggs)
Not every parental histone modification is passed to a child
The G2-to-M-phase transition involves cyclin B/cdc2
p53, a tumour suppressor, activates p21, which halts the cell cycle (this is the DNA damage response pathway)
Wee1 inhibits (not activates) cdc2
PLK1 is activated by cyclin B/cdc2 to promote M phase entry
Epigenetics, DNA methylation, microRNAs, and signal transduction all play roles in cancer formation
The modern understanding of genetics: phenotypes result from genotype, environmental triggers, and chance
Epigenetic drugs (HDAC inhibitors, DNA methyltransferase inhibitors) are used in cancer treatment because they can reactivate silenced tumour suppressor genes. Understanding histone modifications also matters in developmental biology, since the same genome produces hundreds of different cell types through epigenetic programming.
Students often list H1 as a core histone. H1 is the linker histone; the core four are H2A, H2B, H3, and H4.
Students frequently assume that DNA wraps around the nucleosome exactly twice. The correct number is 1.65 times.
Students confuse bromodomains (read acetylation, associated with activation) with chromodomains (read methylation, associated with silencing). A mnemonic: Bromo-Acetyl (both have "a" sounds).
Students sometimes think HATs add new amino acids to histones. HATs add acetyl groups to existing lysine residues.
⚠️ Know the core histones (H2A, H2B, H3, H4) vs. H1. If a question lists H1 as a core histone, it is the false statement.
⚠️ Acetylation = activation; methylation = silencing (as a general rule for histone tails). This comes up repeatedly.
⚠️ Bromodomains bind acetylated lysines; chromodomains bind methylated lysines. These are opposite pairs.
⚠️ DNA wraps around the nucleosome 1.65 times, interacting with the minor groove non-specifically.
⚠️ The zigzag (two-start) model is the predominant higher-order structure in eukaryotes, not the solenoid.
⚠️ PCNA guides histones onto newly synthesised DNA; it is not just a replication clamp.
True or False: H1 is one of the four core histone proteins of the nucleosome.
Fill in the blank: Acetylation of histone tails generally leads to ______, while methylation generally leads to ______.
True or False: Bromodomains recognise methylated lysines on histone tails.
Fill in the blank: DNA wraps around the nucleosome ______ times.
True or False: In the semiconservative model of histone inheritance, one daughter strand receives all the old histones.
Q: Which amino acids project outward from histone proteins and interact with DNA?
A: Mostly lysines and arginines (positively charged, basic amino acids).
Q: What is the histone code?
A: The different modifications on the histone N-termini that can be read by proteins with chromo or bromodomains, influencing gene expression.
Q: What does HAT do to histones?
A: HATs add acetyl groups to lysine residues on histone tails, decreasing histone-DNA interactions and activating gene transcription.
Q: Which model of higher-order chromatin structure is most commonly observed in eukaryotes?
A: The zigzag (two-start) model.
Q: What accounts for the discrepancy between the measured linking number change (-1.2) and the predicted value (-1.65) for DNA in the nucleosome?
A: DNA in the nucleosome has more base pairs per turn than free DNA, which partially compensates for the negative writhe.
Q: What is TRUE regarding the passage of epigenetic information to offspring?
A: Cells are remodified as they differentiate from the blastocyst to a specific cell type (epigenetic marks are reset and re-established during development).
Histone modifications connect back to genome organisation (Part 1), since the fraction of the genome that is transcriptionally active depends on chromatin state. The p53 pathway and cell cycle regulation connect to the checkpoint material in Part 2. This section also bridges to DNA replication (Ch. 9), because nucleosome assembly and histone inheritance must occur alongside replication fork progression. The cancer and epigenetics content ties into broader medical genetics.
nucleosome, histone octamer, H2A, H2B, H3, H4, H1, linker histone, histone tails, lysine, arginine, acetylation, methylation, HAT, histone acetyltransferase, HDAC, bromodomain, chromodomain, histone code, 10 nm fibre, 30 nm fibre, solenoid model, zigzag model, two-start, euchromatin, heterochromatin, DNA methylation, epigenetics, PCNA, nucleosome positioning, semiconservative histone inheritance, asymmetric histone inheritance, p53, p21, cdc2, cyclin B, Wee1, PLK1, cancer epigenetics, chromatin remodelling