Histone Biology and Chromatin Structure

Chromatin Structure

• Chromatin is the complex of DNA and proteins that makes up chromosomes.
• DNA from all 46 chromosomes is approximately 2 meters long, but fits into a nucleus that is 6 micrometers in diameter.
• This packaging is achieved through several levels of organization, starting with the nucleosome.

Nucleosomes

• The fundamental unit of chromatin packaging is the nucleosome.
• A nucleosome contains an octamer of histone proteins (two copies each of H2A, H2B, H3, and H4).
• About 146 base pairs of DNA wrap around this histone octamer.
• The DNA wraps around the histone octamer in a left-handed direction, forming a "beads-on-a-string." structure
• The linker histone, H1, is involved in the next level of compaction in forming the 30-nm fiber.

30-nm Fiber

• Nucleosomes coil to form a 30-nanometer fiber, further compacting the DNA.
• Histone H1 plays an important role in packaging DNA into the 30-nm fiber.
• The core histone tails also contribute to the formation of this fiber, though the exact mechanism isn't yet fully understood

Higher-Order Structures

• The 30 nm fiber is then further compacted, with loops of chromatin tethered to a protein scaffold.
• This process leads to the formation of chromosomes, which are visible during mitosis and meiosis.

Mitotic Chromosome

• During cell division (mitosis), chromosomes are highly condensed and tightly packaged.
• This highly compacted structure is necessary for accurate chromosome segregation during cell division..

Karyotyping

• A karyotype is a visual display of an organism's chromosomes, arranged according to size and banding patterns.
• Karyotypes are typically made from cells undergoing mitosis, where chromosomes are condensed and visible.

Chromatin Regions

• Different regions of chromatin have specialized functions.

• Centromeres are important for chromosome segregation during cell division.

• This region contains repetitive sequences (often alpha-satellite DNA repeats).

• The centromere also contains histone H3 variants, including CENP-A.

• Telomeres are located at the ends of chromosomes.

• Telomeres consist of repeating DNA sequences.

• Telomeres protect the ends of chromosomes from degradation and fusion with other chromosomes. Telomere regions also bind proteins that protect ends and maintain length.

Epigenetics

• Epigenetics is the study of heritable changes in gene expression that don't involve alterations in the underlying DNA sequence.
• This includes modifications like DNA methylation and histone modifications that affect chromatin structure and gene expression, but do not change the DNA sequence itself.
• Epigenetic changes are often influenced by environmental factors and can lead to important phenotypes.
• Chemical modifications of histones influence the activity level of chromatin and subsequently gene expression. This includes:
  • Methylation
  • Acetylation
  • Phosphorylation
  • Ubiquitination

Nucleosome Remodeling

• Nucleosome remodeling complexes are able to change the location of nucleosomes and in turn control accessibility of DNA regions.
• ATP-dependent nucleosome remodeling complexes are able to slide, remove or expose DNA binding areas.
• This complex is important for gene regulation in both eukaryotes and prokaryotes

Medical Relevance

• Some diseases and disorders are linked to abnormalities in chromatin structure.
• Mutations in proteins involved in chromatin structure have important implications in diseases.