Nucleosome Structure and Function

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What Is a Nucleosome
A nucleosome is a structure consisting of DNA wound around histone proteins, somewhat resembling beads on a string.

The nucleosome is a fundamental unit of chromatin, the substance within a chromosome. Composed of DNA wound around a core of histone proteins, it plays a crucial role in DNA packaging and regulation within the cell.

History and Discovery

Don and Ada Olins first observed nucleosomes using an electron microscope in 1974. That same year, Roger Kornberg proposed the concept of the nucleosome as a repeating unit consisting of DNA and histones. The initial evidence came from the digestion of chromatin with nucleases, suggesting that DNA associates with proteins in a regular, repeating structure. In 1988, multiple teams demonstrated that nucleosomes regulate transcription. The first crystal structure of the nucleosome was determined in 1997 by a team led by Timothy Richmond, providing detailed insights into its architecture.

What Is a Nucleosome?

A nucleosome is essentially a segment of DNA wound around a core of eight histone proteins. This structure efficiently packages the DNA into the small confines of the cell nucleus and plays a pivotal role in transcription and gene regulation. By controlling the accessibility of certain DNA regions, nucleosomes influence gene expression and affect various cellular processes.

Functions of Nucleosomes

Nucleosomes are more than mere DNA packaging entities; they are dynamic structures playing a vital role in gene expression regulation. Understanding nucleosome structure and function is crucial in molecular biology and genetics because it sheds light on fundamental processes like transcription regulation, DNA repair, and replication.

  1. DNA Packaging: One of the primary functions of nucleosomes is compacting the long DNA molecules so they can fit within the cell nucleus.
  2. Gene Regulation: Nucleosomes regulate gene expression by controlling the accessibility of DNA to transcription factors and other regulatory proteins.
  3. Epigenetic Regulation: Histone modifications, such as methylation and acetylation, serve as epigenetic marks that influence chromatin structure and function, thereby affecting gene expression.

The study of nucleosomes continues to be a significant area of research, especially in the context of understanding diseases like cancer that often involve alterations in chromatin structure and function.

Nucleosome Structure

The nucleosome core particle consists of approximately 147 base pairs of DNA wrapped around a histodisc, which is a complex of eight histone proteins (two each of H2A, H2B, H3, and H4). The H1 histone stabilizes the DNA-histone interaction and is often referred to as the linker histone. It binds to the DNA between nucleosomes, helping compact the chromatin further.

The DNA does not uniformly wrap around the histones. Instead, it follows a specific, left-handed superhelical path. This path of the DNA around the histones is critical as it influences how tightly the chromatin packs and how accessible the DNA is for transcriptional machinery.

Nucleosome Assembly

Nucleosome assembly is a crucial process in the organization of chromatin in eukaryotic cells. This process involves the orderly association of DNA with histone proteins to form the nucleosome, the fundamental unit of chromatin. Here are the key steps involved in nucleosome assembly:

Steps of Nucleosome Assembly
(David O Morgan)
  1. Histone Synthesis and Modification:
    • The cytoplasm is the site of synthesis of histone proteins (H2A, H2B, H3, and H4).
    • Before assembly, these histones undergo post-translational modifications, which affect nucleosome assembly and function.
  2. Histone Chaperones and Transport:
    • Histone chaperones are specialized proteins that bind to histones. They facilitate proper folding and preventing nonspecific interactions.
    • These chaperones also help in the transport of histones from the cytoplasm to the nucleus.
  3. Formation of Histone H3-H4 Tetramers:
    • Inside the nucleus, two H3 and two H4 histones come together and form an H3-H4 tetramer.
    • This tetramer is the initial seed for nucleosome assembly.
  4. DNA Binding:
    • The H3-H4 tetramer binds to DNA. Histone chaperones facilitate this interaction and aid in positioning the tetramer on the DNA.
    • The binding of the H3-H4 tetramer to DNA is the first step in the formation of the nucleosome structure.
  5. Incorporation of H2A-H2B Dimers:
    • After the H3-H4 tetramer binds to DNA, two H2A-H2B dimers associate with this complex.
    • The addition of H2A-H2B dimers completes the histone octamer, around which the DNA fully wraps.
  6. DNA Wrapping:
    • Approximately 147 base pairs of DNA wrap around the histone octamer in 1.65 left-handed superhelical turns.
    • Histone chaperones mediate the DNA wrapping process. This involves the sequential bending and positioning of the DNA.
  7. Linker Histone Binding:
    • The H1 histone (linker histone) binds to the DNA as it enters and exits the nucleosome core.
    • The H1 histone stabilizes the nucleosome structure and contributes to higher-order chromatin organization.
  8. Maturation and Chromatin Remodeling:
    • Once nucleosomes form, they undergo further maturation through histone modifications like methylation, phosphorylation, and acetylation.
    • Chromatin remodeling complexes also reposition nucleosomes on DNA, affecting chromatin structure and accessibility.

Each of these steps is tightly regulated and critical for proper chromatin function, including gene expression, DNA replication, and repair. The precise orchestration of nucleosome assembly is essential for maintaining genomic integrity and cellular homeostasis.

References

  • Kornberg, R.D. (1974). “Chromatin structure: a repeating unit of histones and DNA”. Science. 184 (4139): 868–871. doi:10.1126/science.184.4139.868
  • Lorch, Y.; LaPointe, J.W.; Kornberg, R.D. (1987). “Nucleosomes inhibit the initiation of transcription but allow chain elongation with the displacement of histones”. Cell. 49 (2): 203–210. doi:10.1016/0092-8674(87)90561-7
  • Olins, A.L.; Olins, D.E. (1974). “Spheroid chromatin units (v bodies)”. Science. 183 (4122): 330–332. doi:10.1126/science.183.4122.330
  • Reece, J.; Campbell, N. (2006). Biology. San Francisco: Benjamin Cummings. ISBN 978-0-8053-6624-2.
  • Teif, V.B.; Clarkson, C.T. (2019). “Nucleosome Positioning”. Encyclopedia of Bioinformatics and Computational Biology. 2: 308–317. doi:10.1016/B978-0-12-809633-8.20242-2