L3-4 Karyotypes and Cancer Biology

Chromosomal Characteristics and Cancer Karyotypes

  • Chromosome Identification

    • Chromosomes have different colors enabling identification of different types.

    • Chromosomes are aligned in pairs by computers.

    • Normal karyotypes can be visually assessed for abnormalities.

  • Comparison Between Normal and Cancer Karyotypes

    • Example of Cancer Cell Karyotype: Colon cancer cell karyotype exhibits distinct chromosomal differences.

    • Different numbers of chromosomes were observed.

    • Fragments of chromosomes appear fused.

    • Differences between normal and abnormal karyotypes are significant, particularly in solid tumors.

    • 90% of cancers show phenotypic chromosomal abnormalities such as aneuploidy.

  • Definition of Aneuploidy

    • Abnormal karyotypes demonstrating an abnormal number of chromosomes is termed aneuploidy.

  • HeLa Cells

    • Karyotype of HeLa cells: derived from human cancer patient.

    • Features three copies of chromosome 1 and one of chromosome 2.

    • Staining techniques reveal chromosomal fragments and fusions clearly.

    • Variability of chromosomal abnormalities is present among cancer cells.

  • Mechanisms Behind Aneuploidy

    • The emergence of aneuploidy in cancer cells can be discussed in upcoming lectures.

    • Explored how cancer cells can use aneuploidy as a marker in treatment.

Lecture Structure

  • The structure of upcoming lectures is as follows:

    1. Genome Organization and Epigenetics: Focus on chromosomal organization and its variation in cancer.

    2. Cohesin Complex in Chromosome Biology: Investigate the cohesin complex’s role in cancer.

    3. Aneuploidy and its Consequences: Discuss aneuploidy in detail.

    4. Data from Scientific Studies: Review actual data and scientific research methodologies.

Chromosomal Organization

  • Classical View of Interphase Chromatin Structure

    • Nuclear architecture helps identify chromosomal territories (areas occupied by individual chromosomes).

    • Chromosomal territories are divided into compartments.

  • Topologically Associating Domains (TADs)

    • TADs are defined regions of DNA marked by the presence of cohesin and CTCF proteins.

    • Cohesin holds DNA strands, whereas CTCF delineates the boundaries of chromatin loops.

    • Larger loops may contain smaller loops, emphasizing the hierarchical nature of chromatin structure.

  • Differences Between Interphase and Mitotic Chromosomes

    • Notable differences between chromatin loops in interphase and mitotic phases.

    • Mitotic chromosomes use condensin proteins rather than cohesin and CTCF.

Transcriptional Regulation in Cancer

  • Active vs. Inactive Chromatin Compartment

    • Chromatin can be transcriptionally active (pink) or inactive (green).

    • Transcriptional activators can move fragments of chromatin from inactive to active compartments, impacting gene expression.

    • Conversely, genes may shift to inactive compartments upon repression.

  • Dynamics of DNA and Chromatin Structure

    • Gene activation or repression requires chromatin to open, allowing transcription factors access to the DNA.

    • Enhancers can affect genes located far away in a linear fashion due to physical looping of DNA.

Proto-Oncogenes and Cancer Development

  • Definition of Proto-Oncogenes

    • Proto-oncogenes are normal genes that, when mutated, can lead to cancer develop into oncogenes.

    • Processes leading to this transformation include mutations, gene fusions, and enhancer hijacking.

  • Impact of Chromatin Loops on Gene Expression

    • Changes in chromatin loop boundaries can lead to activation of proto-oncogenes.

    • Proteins like CTCF are often mutated in cancer and play a role in regulating chromatin loops and gene expression.

Histone Modifications and Epigenetics

  • Nucleosome Structure

    • Core of nucleosomes consists of histones (H2A, H2B, H3, H4).

    • Histone tails are flexible and subject to post-translational modifications (PTMs).

  • Types of Histone Modifications

    • Histone modifications include phosphorylation, methylation, acetylation, and ubiquitination.

    • PTMs can influence transcriptional activity (e.g., acetylation often activates genes, while methylation may silence them).

  • Histone Code Theory

    • Theory states certain modifications correlate with specific biological functions.

    • Writers add modifications, readers recognize them, and erasers remove them.

Epigenetics in Cancer

  • Changes in histone variants and PTMs contribute significantly to cancer biology.

    • Different variants may facilitate or inhibit tumor growth based on their functional roles.

  • Mechanism of Gene Expression Changes in Cancer

    • Distinctions in signaling pathways and protein functions occur when chromatin organization changes.

    • Cancer has a genetic basis, evident in altered gene expression patterns.

Therapeutic Implications of Epigenetic Modifications

  • Current Developments in Cancer Treatment

    • Targeting histone and DNA modifications offers promising strategies for therapy.

    • Inhibitors for enzymes involved in writing and erasing marks are being developed.

  • Impact of Histone Mutations in Cancer

    • Recent findings highlight mutations in histone genes contributing to cancer progression, pointing to gaps in previous understandings.

    • Mutated histones may disrupt normal epigenetic functions, propelling malignancy.

Conclusion

  • Summary: Cancer involves significant alterations in genomic architecture and gene expression driven by complex interactions between genetic and epigenetic factors.