Sandbox 135

Introduction

Nuclear chromosomes are compressed as small packages of nucleosomes. DNA is wrapped twice around the nucleosome, which is made of a histone octamer (H2A, H2B, H3, H4) core. The tightly compacted chromosome does not allow gene expression to occur.

Expressing these compacted areas of the chromosome relies upon the modification of histones. This modification can occur in the histone tail, which are flexible, irregular chains present at the C-terminal.

The modified tail can become the site for Transcription Factors (TF), which interacts with specific genes that undergo gene expression. TF first binds to the promoter region in the DNA, recruiting RNA polymerase II and setting a foundation for Co-Activator TF to bind to the basal TF. This event finally binds the Activator TF to an enhancer region in the DNA, increasing the rate of transcription. This process allows for transcription to begin.

p300 is a transcriptional coactivator that regulates gene expression through the use of HAT and BRD. p300 contains a HAT domain and a bromodomain which are 380 residues and 110 residues respectively.

How Do HAT and BRD Function?

HAT proteins in the nucleus are well regulated, which allows for acetylation to occur where needed.

In the active site hydrogen bonds hold the substrate (Lysine of the histone tail) in place, Lys1456 with Trp1436 and Acetyl-CoA with Tyr1467.

Alignment of the Lysine and Acetyl-CoA requires the L1 loop to be in position and an interaction between CoA and the HAT domain. An electrostatic attraction of the negative grove of the HAT with surrounding amino acids of the histone tails is also required for alignment.

The acetyl group, found in Acetyl-CoA, is transferred to the Lysine in the histone tail.

Bromodomain

Once the Lysine is acetylated the bromodomain is able to bind.

After the bind between Lysil and bromodomain occurs, transcription factors and RNA Polymerase II are recruited, necessary for gene expression.