Transcription Regulation in Eukaryotes

Transcription Regulation (Eukaryotic)

• Physical interactions occur between promoters (near genes) and enhancers (far from genes).
• Cis regulatory interactions are encouraged by cohesion ring looping.
• Enhancers and promoters are linked by sequence-specific transcription factors (TFs), co-regulators, mediator complex, and polymerase. The process culminates in a complex involving ~56 polypeptides, general TFs, TFIID TAFs, and mediator.
• The Polymerase CTD may interact with the mediator complex.

Transcription Factors (TFs)

• Sequence-specific TFs regulate specific genes based on their sequence.
• Different binding domains include Zinc-Finger (e.g., CTCF), Leucine zipper, Helix-turn-helix.
• Master developmental regulators and reprogramming factors (e.g., fibroblast to muscle/neuron) are TFs.
• TFs bind nucleosomes, but often destabilize DNA structure.
• Pioneer TFs bind with high affinity, increasing nucleosome accessibility for other TFs.

Enhancers

• Enhancers typically range from 1 kb to 1 Mb away from target genes.
• Located upstream or downstream of genes.
• Orientation of enhancers is independent.
• Super-enhancers are clusters of enhancers that regulate pluripotency genes/oncogenes.
• Epigenetic signatures (e.g., H3K27ac) and lack of nucleosomes can identify enhancers.

Nucleosomes

• Nucleosomes are the fundamental units of chromatin. DNA wraps around histone octamers (2 each of H2A, H2B, H3, and H4).
• Organization proceeds from 10nm beads-on-a-string, to 30nm fibers (zigzag or solenoid), to 300-700 nm chromatids and ultimately to 1400 nm chromosomes.
• Nucleosomes are absent at active promoters and enhancers, which are therefore nucleosome-depleted regions (NDRs).
• Histone octamers are comprised of two H2A-H2B dimers and two H3-H4 dimers.
• DNA wraps around the histone core in a left-handed manner, forming nucleosome core particles (NCPs). Histone tails are unstructured and are often modified.

Chromatin Remodeling

• Chromatin remodeling can involve spontaneous unwrapping/sliding.
• Or be ATP-driven, using factors from families like SNF2, CHD1, ISWI, and INO80 (distinct activities termed pushers (SWI/SNF), pullers (ISW2), and spacers (ISW1)).
• Histone modification (acetylation, methylation) is a mechanism of transcription regulation.

Chromatin Structure

• Two models for chromatin configuration exist: a zigzag model and a two-start helix model.
• Various post-translational modifications (PTMs) on histone tails can influence DNA binding and consequently the chromatin state.