DNA is organized into chromatin by wrapping around a core made of four different histone proteins to form nucleosomes. Nucleosomes interact with each other to form larger structures that pack into chromatin, which controls access to the wrapped DNA. Dynamic post-translational modifications of the histone proteins alter the way in which these proteins interact with each other or with DNA, and thus regulate countless biological processes.

 

The Ottesen Laboratory is developing a synthetic toolkit using peptide and protein ligation chemistry that allows us to determine the effects of histone modifications on nucleosomes and chromatin, and how these modifications regulate important cellular functions like gene regulation and DNA repair.

 

Histone Acetylation in Regulation of Biological Function

The nucleosome core is coated with positively charged lysine side chains that interact with the phosphate backbone of DNA. Acetylation of a lysine side chain both removes a positive charge and adds steric bulk.  When this occurs in certain regions of the DNA-histone interface, we find that it weakens interactions that stabilize the nucleosome. This in turn changes the properties of chromatin, with implications for proteins (such as DNA repair machinery) that must clear nucleosomes from DNA in order to carry out their functions.

 

We have openings for students or postdoctoral researchers in several projects related to this work, including modifications at protein-protein interfaces in the nucleosome, and determining how modifications at various positions along the DNA-histone interface control where nucleosomes are positioned on DNA sequences.

 

Histone Phosphorylation and Chromatin Remodeling

The effects of most histone modifications are fairly subtle. However, we have identified a phosphorylation site in the histone-DNA interface that appears to dramatically alter the nucleosome structure. We believe that phosphorylation at the histone-DNA interface may be a general mechanism for regulation and maintenance of chromatin remodeling. We have openings for researchers in this area.