UNCOVERING THE BIOPHYSICAL MECHANISMS OF HISTONE COMPLEX ASSEMBLY

Abstract

At the most basic level, inheritance in living beings occurs by passing the genomic information such as the DNA sequences from the parent generation to the offspring generation. Hence, it is a fundamental goal for every generation to efficiently express the genomic information and safely pass it on to the next generation. In human and other eukaryotic species, this mission is mediated via chromatin, a macromolecule with intricate hierarchical structure. The fundamental unit of chromatin is called a nucleosome, a complex of histone proteins wrapped around with DNA. To carry out diverse biological functions such as transcription and DNA replication, the DNA-protein complex must dynamically transition between more compact, closed states and more accessible, open ones. To fully understand the chromatin structure and dynamics, it is essential to comprehend the basic structural unit of chromatin, nucleosome. In this dissertation, I present my doctoral research in the exploration of the nucleosome dynamics problem, focusing on the assembly process of histone proteins. From histone monomer to dimer, then to tetramer, octamer, and nucleosome, I used different computational modeling theories and techniques, together with different experimental collaborations, to investigate the overall thermodynamics and specific mechanistic details of nucleosome dynamics at different levels. My work has shed light on the fundamental principles governing the histone protein folding and histone complex assembly, in particular, highlighting similarities and differences between the canonical and variant CENP-A histones.