Assistant Professor
Role and establishment of histone modifications
Chromatin structure
In our lab we are interested in understanding chromatin biology.
In particular we would like to know: How do histone post-translational
modifications influence chromatin structure? How do these modifications
modulate binding of chromatin-associated proteins? And how are they
established? To address these questions we are using chemical, biochemical,
and biophysical techniques, with an eye toward bringing insights we
gain in vitro to discoveries in vivo.
In eukaryotic organisms, DNA does not exist free in cells, but instead
is present as chromatin, a complex assembly of DNA, histone proteins,
and chromatin-associated proteins. Chromatin exist in a hierarchy of
structures:
From its structure it is clear that chromatin provides a means to store
DNA. However, chromatin also provides a platform for regulating the
underlying DNA. In fact, nearly all DNA-mediated processes are regulated
at the chromatin level, including transcription, repair, and replication.
Not surprisingly misregulation of chromatin can lead to disease states,
such as various cancers and congenital defects.
One way chromatin acts as a regulatory platform is through post-translational
modification of histones. These modifications include acetylation, phosphorylation,
methylation, ubiquitination, and ADP-ribosylation and can occur at over
50 identified histone residues:
To study the effects of these modifications in vitro, we have developed
a native chemical ligation strategy to generate H3 and H4 histone proteins
with specific amino-terminal tail modifications. These histones are
then incorporated into more complex chromatin structures for study.
One of the current focuses in our lab is to understand the functional
and mechanistic role of histone acetylation. Histones are reversibly
acetylated at numerous residues, and these marks play a role in transcriptional
activation, establishment of euchromatic and heterochromatic domains,
DNA damage repair, and initiation of replication. We have recently discovered
that a single acetylation event on histone H4 lysine 16 is sufficient
to disrupt several levels of higher-order chromatin structure. We are
currently trying to better understand how this occurs mechanistically,
how other histone modifications affect this disruption, and how this
mark directs modification of other residues.
Other areas of research in our lab include understanding the role of
histone methylation in facilitating heterochromatin formation, how proline
isomerization influences histone function, and identifying the biological
function of uncharacterized histone modifications.
