Human DNA: total length ~2 metres (200 cm) of DNA in every cell nucleus only ~6 μm in diameter. This requires ~50,000-fold compaction. Without packaging: DNA would be impossibly tangled and unmanageable. Solution: DNA is packaged around histone proteins into a hierarchical structure: DNA → nucleosome (beads-on-a-string) → 30 nm fibre (solenoid) → looped domains → scaffold-associated chromatin → metaphase chromosome. The basic unit is the nucleosome. Each level of compaction contributes ~6-7 fold, and together achieve the ~50,000-fold compaction needed to fit 2 m of DNA into 6 μm nucleus.

Nucleosome = basic unit of chromatin. Core particle: 147 bp of DNA wound 1.65 turns around a histone octamer. Histone octamer: (H2A-H2B)₂ + (H3-H4)₂ tetramer → 8 histone molecules. Linker DNA: 20-80 bp connects adjacent nucleosome cores. H1 (linker histone): binds where DNA enters/exits the nucleosome core → seals the two turns → promotes higher-order folding. Diameter of nucleosome: ~11 nm. Bead-on-string appearance in electron microscopy (low ionic strength conditions). First described by Roger Kornberg (1974) — Nobel Prize 2006. Each human cell has ~30 million nucleosomes. Packing ratio at nucleosome level: 7-fold compaction.

Histones: small, basic proteins (basic = net positive charge at physiological pH). Rich in positively charged amino acids: lysine (Lys, K) and arginine (Arg, R). These positive charges interact electrostatically with the negative charges of DNA phosphate groups → strong but reversible ionic bonds. Five types: H1 (linker), H2A, H2B, H3, H4 (core histones). H3 and H4 are most conserved (nearly identical across all eukaryotes — even yeast and human H4 differ by only 2 amino acids). H1 is most variable. Evolutionary conservation of H3 and H4 reflects their critical role in nucleosome structure. Histones are NOT found in prokaryotes (no nucleosomes in bacteria) — bacteria use histone-like proteins (HU, H-NS) for DNA compaction. Exception: some archaebacteria have true histones.

30 nm fibre (solenoid): nucleosomal arrays condense with H1 → 30 nm diameter fibre. 6 nucleosomes per turn of solenoid. ~40-fold compaction total. Looped domains: 30 nm fibre forms loops (50-100 kb each) anchored to nuclear scaffold. Scaffold = non-histone chromosomal (NHC) proteins: topoisomerase II, condensins, cohesins. ~1000-fold compaction. Metaphase chromosome: further condensation during mitosis. Condensins compact the looped domains → 300 nm and then 700 nm fibres → ~50,000-fold compaction. Euchromatin vs heterochromatin: euchromatin (less condensed, transcriptionally active). Heterochromatin (highly condensed, transcriptionally silent). Centromeres and telomeres = constitutive heterochromatin. Inactive X (Barr body) = facultative heterochromatin.

Histone modifications regulate gene expression without changing DNA sequence = epigenetic regulation. Modifications occur on N-terminal histone tails protruding from nucleosome. Types: Acetylation (by HATs = histone acetyltransferases): adds -COCH₃ to lysine → neutralises positive charge → loosens DNA-histone interaction → opens chromatin → promotes transcription. Removed by HDACs (histone deacetylases). Methylation (by HMTs): adds -CH₃ to lysine or arginine. Can activate OR repress depending on residue and degree. H3K4me3 = active transcription. H3K27me3 = gene silencing. Phosphorylation: serine/threonine. H3S10ph = mitosis marker. Ubiquitination: large modification that alters chromatin structure. The 'histone code' hypothesis: combinations of modifications determine gene activity. Cancer epigenetics: abnormal histone modification patterns → inappropriate gene expression → cancer development.

Chromatin remodelling complexes use ATP to move, eject, or restructure nucleosomes to control DNA accessibility. Types: SWI/SNF complex: slides nucleosomes to expose regulatory DNA sequences. ISWI complex: evenly spaces nucleosomes for uniform chromatin. NuRD complex: deacetylates histones AND remodels chromatin → repression. Importance: transcription factors need access to DNA → nucleosomes must be moved. DNA repair: damage site must be accessible to repair enzymes. Replication: nucleosomes must be disassembled ahead of the replication fork. During transcription: RNA polymerase must traverse nucleosomes → remodelling complexes help by temporarily displacing histones. Pioneer transcription factors: special TFs that can bind nucleosomal DNA without remodelling first (e.g., FoxA, GATA).

Prokaryotic: circular DNA in nucleoid region. No membrane-bound nucleus. No histones (eubacteria). Histone-like proteins: HU (most conserved), H-NS, IHF, Fis → compact DNA using different mechanisms. Supercoiling: topoisomerases maintain DNA supercoiling for compaction. DNA-binding proteins form nucleoid-associated protein (NAP) complexes. Much less compaction needed (few million bp vs 3 billion in humans). Eukaryotic: linear chromosomes in membrane-bound nucleus. True histones (H1, H2A, H2B, H3, H4). Nucleosome-based compaction → 50,000-fold. Complex regulation through histone modifications. Archaea: remarkably, some archaea (Methanobacterium, Methanothermus) have true histone proteins forming archaeal nucleosomes → supports Archaea-Eukarya evolutionary relationship.

Watson-Crick B-DNA (most common under physiological conditions): right-handed double helix. Diameter: 2 nm (20 Å). Rise per base pair: 0.34 nm (3.4 Å). Base pairs per turn: 10 bp. Pitch (distance per complete turn): 3.4 nm. Major groove (wide, 2.2 nm) and minor groove (narrow, 1.2 nm). Proteins typically bind in major groove (more information per groove). A-DNA: right-handed, shorter and wider, 11 bp/turn, found in dehydrated conditions, RNA-DNA hybrid. Z-DNA: left-handed, 12 bp/turn, found in GC-rich regions under high salt, may have regulatory role. G-quadruplex: non-Watson-Crick structure in G-rich telomeric sequences, four guanines form planar G-quartet. i-motif: C-rich strands under acidic conditions. These non-B forms may have regulatory roles in transcription and replication.