The Role of Histone Chaperones in Histone Acetylation and Nucleosome Dynamics

PROJECT SUMMARY
There is a fundamental paradox within the nucleus of every eukaryotic cell: The genetic material must be
organized and compacted yet remain accessible for readout by transcription machinery. Two of the many factors
that retain this balance are histones and histone binding proteins. Histones are ultimately responsible for
compacting the chromosomal DNA almost 500,000-fold to fit into the nucleus. While genome accessibility is
regulated in part by the actions of histone acetyltransferases (KATs), histone chaperones interact directly with
histones and can assemble and/or disassemble them on DNA. KATs covalently modify the histones and
therefore, have the potential to alter chromatin structure. Exciting new evidence structurally and functionally link
KATs and histone chaperones. However, virtually nothing is known about the mechanisms by which these
proteins cooperate to manage compaction and genome accessibility. To elucidate these mechanism(s) we are
studying the relationships between two families of histone chaperones in yeast and humans, Nap1 and Asf1,
and their corresponding KATs, Rtt109 (yeast) and CBP and p300 (human). Rtt109 is the structural homolog of
CBP/p300, and both KATs are functionally linked to the Nap1 and Asf1 families of histone chaperones. We have
demonstrated the ability of histone chaperones (Asf1), to recognize the acetylation state of histones and work
together to modify the specificity of KATs. We are proposing that these chaperones function to maintain the
proper acetyl-profiles of chromatin by regulating both which lysines get acetylated and their incorporation in to
chromatin. A biochemical and molecular understanding of how specificity and selectivity is achieved is currently
a major challenge in the chromatin field. This project will employ and expand on new methodologies for studying
complex protein-protein networks needed to regulate chromatin dynamics and post-translational specificity.

Grant Number: 5R01GM102503-10
NIH Institute/Center: NIH
Principal Investigator: Andrew Andrews