Explain the role of transcription factors associated with transcription initiation, elongation and termination. How does Histone modification regulate chromatin accessibility?

Transcription Factors and Their Roles

Transcription factors are proteins that bind to DNA and regulate gene expression. They can be broadly categorized based on their function during the transcription process:

Transcription Initiation

• General Transcription Factors (GTFs): These are essential for the initiation of transcription at all promoters. Examples include TFIID (containing the TATA-binding protein - TBP), TFIIB, TFIIF, TFIIE, and TFIIH. TFIID binds to the TATA box, initiating the assembly of the pre-initiation complex (PIC).
• Activators: These TFs bind to enhancer regions and increase transcription. They often function by recruiting co-activators, which modify chromatin structure or interact with GTFs. An example is the glucocorticoid receptor, activated by steroid hormones.
• Repressors: These TFs bind to silencer regions and decrease transcription. They can compete with activators for binding sites or recruit co-repressors that modify chromatin to a repressive state. An example is Mad-Max, involved in cell cycle regulation.

Transcription Elongation

• Positive Transcription Elongation Factor b (P-TEFb): This TF phosphorylates RNA polymerase II, releasing it from promoter-proximal pausing and allowing it to efficiently elongate the transcript.
• Elongator complex: This complex enhances the processivity of RNA polymerase II, ensuring efficient transcription of long genes.

Transcription Termination

• Cleavage and Polyadenylation Specificity Factor (CPSF): This TF recognizes the polyadenylation signal (AAUAAA) in the RNA transcript and initiates cleavage of the RNA.
• Cleavage Stimulation Factor (CstF): Works with CPSF to ensure accurate RNA cleavage.
• Terminator: Some TFs directly bind to terminator sequences, halting RNA polymerase II progression.

Histone Modification and Chromatin Accessibility

DNA is packaged into chromatin, a complex of DNA and proteins (primarily histones). The structure of chromatin significantly impacts gene accessibility. Histone modifications are covalent changes to histone proteins that alter chromatin structure and gene expression.

Types of Histone Modifications

• Acetylation: Addition of acetyl groups (COCH3) to lysine residues, typically associated with increased gene expression. Acetylation neutralizes the positive charge of histones, reducing their affinity for negatively charged DNA, leading to a more open chromatin structure (euchromatin). Enzymes involved include Histone Acetyltransferases (HATs).
• Methylation: Addition of methyl groups (CH3) to lysine or arginine residues. Methylation can have activating or repressive effects depending on the specific residue modified. For example, H3K4me3 is associated with activation, while H3K9me3 and H3K27me3 are associated with repression. Enzymes involved include Histone Methyltransferases (HMTs).
• Phosphorylation: Addition of phosphate groups (PO4) to serine, threonine, or tyrosine residues. Often involved in signaling pathways and can influence chromatin structure and gene expression.
• Ubiquitylation: Addition of ubiquitin molecules. Can regulate gene expression and protein degradation.

How Histone Modifications Regulate Chromatin Accessibility

Histone modifications recruit other proteins that further alter chromatin structure. For example:

• Bromodomains: Recognize acetylated histones and promote chromatin opening.
• Chromodomains: Recognize methylated histones and can lead to chromatin compaction or recruitment of repressive complexes.
• SWI/SNF complexes: ATP-dependent chromatin remodelers that can alter nucleosome positioning and chromatin structure.

The interplay between histone modifications and transcription factors is crucial. For instance, activators often recruit HATs to acetylate histones, increasing chromatin accessibility and promoting transcription. Conversely, repressors can recruit HMTs to methylate histones, leading to chromatin compaction and transcriptional silencing.

Histone Modification	Effect on Gene Expression	Enzymes Involved
H3K4me3	Activation	Histone Methyltransferase (MLL complex)
H3K9me3	Repression	Histone Methyltransferase (SUV39H1)
H3K27me3	Repression	Polycomb Repressive Complex 2 (PRC2)
H3 acetylation	Activation	Histone Acetyltransferases (HATs)