Histones: Form octamers around which DNA coils, creating a repetitive “beads on a string” structure. This winding pattern contributes significantly to chromatin compaction.
Nonhistone chromosomal proteins: Encompass all other proteins associated with the chromosome, performing diverse roles such as regulation, enzyme activity, and structural support.
Single-copy versus repetitive DNA
Some DNA sequences occur only once (single-copy), while others are present in multiple copies (repetitive DNA).
Tandem repeats are repeated sequences aligned consecutively (e.g., CAGCAGCAG).
Excessive trinucleotide repeats can lead to disorders like Huntington disease or fragile X syndrome.
Satellites, minisatellites, microsatellites: Clusters of repeated sequences whose distinctive patterns can aid in paternity testing, forensic analysis, or verifying bone marrow engraftment by matching donors to recipients.
Interspersed repeats: Generated by mobile genetic elements such as transposons, which often carry repetitive DNA at both ends and can move within the genome.
Supercoiling
Supercoiling refers to an additional twist (coil) introduced onto the already helical DNA. This higher-order coiling helps compress a significant length of DNA into a chromosome, enabling it to fit within the cell nucleus.
Chromatin vs. chromosome
Chromatin is the complex of DNA plus associated proteins (histones and others). When highly condensed and visible under a microscope (e.g., during mitosis), this structure is referred to as a chromosome.
During interphase, eukaryotic chromosomes exhibit two regions that differ in density and function:
The densely packed heterochromatin—typically located at centromeres and telomeres—generally contains inactive genes.
The loosely arranged euchromatin houses actively transcribed genes, with DNA wrapped around nucleosomes but not further compacted.
Control of gene expression in prokaryotes
Prokaryotic gene expression is controlled through both negative and positive regulatory mechanisms:
Negative control, exerted by repressors and co-repressors, reduces transcription
Positive control, driven by inducers and enhancers, increases transcription.
This tightly regulated system allows prokaryotes to adapt quickly to environmental changes by precisely modulating the expression of their genes.
Transcription factors
Transcription factors in prokaryotes bind to regulatory DNA elements such as enhancers and silencers, which are located near the core promoter as part of the extended promoter region.
When activator proteins attach to enhancers, they increase transcription, whereas binding of silencers by repressor proteinsdecreases it.
Operon concept and Jacob-Monod model
A common mechanism for gene regulation in prokaryotes involves operons, which are clusters of genes controlled by a single promoter.
Within an operon, the operator region is the binding site for regulatory proteins. For instance, in the lac operon described by the Jacob-Monod model, a repressor binds to the operator near the promoter, blocking transcription when the appropriate inducer is absent.
Regulation of the lac operon in E. coli
Additional regulation is achieved through molecules known as co-repressors and co-inducers. When a co-repressor binds to its target, it converts an otherwise inactive transcription factor into an active repressor, whereas a co-inducer can either activate an inducer or inactivate a repressor, fine-tuning the transcriptional response.
Gene repression in bacteria
Transcription attenuation is another regulatory strategy, exemplified by the trp operon, where the formation of a specific stem-loop structure in the mRNA causes premature termination of transcription when tryptophan levels are high, while low levels permit full-length transcription.
Diagram of the trp operon regulation in E. coli
Positive control in bacteria
Bacteriophages can commandeer the host’s transcription machinery by producing specialized α factors. These factors are synthesized at different stages of infection, ensuring that early, middle, and late phage genes are transcribed in the proper sequence.
Control of gene expression in eukaryotes
Control of gene expression in eukaryotes
In eukaryotic cells, gene expression is tightly regulated primarily at the transcription and post-transcription levels. Unlike prokaryotes—which rely heavily on operons and attenuation to adjust gene output—eukaryotes employ a broad array of mechanisms involving transcription factors, DNA looping, chromatin modifications, and mRNA processing to fine-tune when and how genes are expressed.
Transcription regulation
Transcription factors, which are specialized DNA-binding proteins, influence the rate at which a gene is transcribed by binding to enhancers (activating sequences) or silencers (repressive sequences). These regulatory regions can be located far from the promoter—often upstream or downstream of the gene—and require the DNA to loop so the bound transcription factor can physically contact the promoter complex. Additional intermediary proteins (co-activators or co-repressors) assist in stabilizing this loop formation and modulating RNA polymerase activity.
DNA-binding domains within these transcription factors typically interact with the major and minor grooves in the DNA double helix. Common motifs that facilitate such binding include the helix-turn-helix, zinc finger, and basic-region leucine zipper.
Helix-turn-helix, zinc finger, and leucine zipper DNA-binding motifs
Gene amplification and duplication
Eukaryotes may also control expression levels through gene amplification or gene duplication, effectively increasing the number of copies of a particular gene. This can occur when chromosomal segments are duplicated or when entire chromosomes are replicated extra times. Amplified genes, such as MYC or RAS in cancer, can drive excessive protein production and influence disease outcomes. Some duplications, like Her2 in breast cancer cells, serve as clinical targets for specific therapies (e.g., Herceptin). In other cases, duplicates have minimal functional impact aside from enlarging the genome.
Post-transcriptional controls
Following transcription, post-transcriptional events shape how much protein is ultimately produced from a given mRNA:
Splicing: Eukaryotic pre-mRNA includes introns (non-coding segments) that are removed and exons (coding segments) that remain, forming mature mRNA. Alternative splicing provides a means for generating multiple mRNA variants (and thus different proteins) from a single gene.
5′ cap and 3′ poly-A tail: A 5′ cap (modified guanine) and a poly-A tail at the 3′ end protect mRNA from degradation and enhance its export from the nucleus.
RNA modifications: Certain RNAs, especially tRNA and rRNA, contain modified nucleotides that help maintain their structural integrity and functional capabilities.
RNA degradation: Finally, cells regulate the rate at which mRNAs degrade. By altering the stability of specific transcripts, the cell can fine-tune protein production over time.
Cancer as a failure of normal cellular controls
In cancer, cells disregard the usual regulatory signals that would curb their growth. Unlike normal cells, which halt division or trigger apoptosis (programmed cell death) upon detecting significant DNA damage, cancer cells continue reproducing under conditions that would typically halt proliferation. They also stimulate angiogenesis, prompting new blood vessels to grow and supply nutrients, and can become “immortal,” evading the typical limit on the number of cell divisions. Another hallmark is metastasis, where cells break away from a primary tumor and form secondary tumors in other body regions.
Oncogenes and tumor suppressors
Oncogenes are genes that, when activated or mutated, push cells into continuous division. In their prior “normal” form, called proto-oncogenes, they often help regulate cell growth or division at appropriate levels. Once converted into oncogenes (for example, src), they can trigger uncontrolled proliferation.
Tumor suppressor genes act as a counterbalance, limiting or checking cell division. If these genes (like p53) lose functionality, cells may proliferate abnormally, contributing to cancerous behavior.
Role of p53 in cell cycle regulation and apoptosis
Regulation of chromatin structure
Chromatin refers to DNA wrapped around histone proteins. The degree of compaction influences gene expression: Euchromatin: Loosely packed, allowing active transcription. Heterochromatin: Tightly packed, reducing gene accessibility.
Cells modulate chromatin by modifying DNA or histones:
DNA methylation: In eukaryotes, CpG islands (areas rich in cytosine and guanine) near promoters are prime targets for methylation by DNA methyltransferase (DNMT). Adding methyl groups (e.g., forming 5-methylcytosine) typically silences the corresponding genes.
Histone modifications: Methylation and acetylation of histones can also shift chromatin between active (euchromatin) and inactive (heterochromatin) states.
Non-coding RNAs
Non-coding RNAs encompass all RNA types except mRNA. These play structural or regulatory roles:
rRNA (ribosomal RNA): Constitutes the ribosome’s core components.
tRNA (transfer RNA): Delivers amino acids during translation.
snRNA (small nuclear RNA): Participates in RNA splicing machinery (spliceosomes).
snoRNA (small nucleolar RNA): Guides chemical modifications in RNA.
miRNA (microRNA): Involved in RNA silencing, either inhibiting mRNA translation or promoting its degradation.
Various modifications, such as 2′-O methylation or conversion of uracil to pseudouracil, help stabilize these RNAs, maintain their structure, or enhance their function.
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