(596h) Effects of Histone Tail Modifications On Chromosome Structure and Activity

The N-terminal regions of histone H3 and H4 proteins play an important role in gene regulation. Abnormal modifications on H3 and H4 tails are associated with various types of cancer diseases, such as lung, prostate and breast cancer. Drug molecules targeting at specific modification sites on H3 and H4 tails provides a viable route for editing aberrant gene transcription pattern. It is therefore of critical importance to understand the role of each histone tail in regulating gene transcriptional activity. We constructed model nucleosomes and nucleosomal arrays with modified H3 and H4 N-terminal tails and examined their respective effects on nucleosome conformation and dynamics using various biophysical experiments. Under different ionic strengths, H3 tails participate primarily in intra-nucleosomal interactions by constraining the DNA breathing motion and limiting its conformational variations. Histone H4 tails, on the other hand, are less effective in regulating the stability of a nucleosome. H4 tails are more involved in inter-nucleosomal interactions. Our results revealed the detailed mechanism as to how H3 and H4 tails are involved in intra- and inter- nucleosomal interactions under different ionic conditions. The findings will facilitate the screening of drug targets on histone tails.