CEGR faculty member Scott Showalter has been awarded two new grants to support
gene regulation research at Penn State.

Dr. Showalter has received a new grant from the National Science Foundation (NSF) to
develop 13 C direct-detect nuclear magnetic resonance experiments that will define the
impact of protein phosphorylation and methylation on structure and interactions in any
protein sequence context. Post-translational modification of disordered protein regions
is a ubiquitous signaling strategy that is central to many of the most well-known
mechanisms in gene regulation. For example, the histone code features extensive
lysine N-methylation and the RNA Polymerase II CTD code is largely driven by serine,
threonine, and tyrosine phosphorylation. Transcription factor phosphorylation is also
abundant and there is emerging evidence that lysine methylation of non-histone
proteins is similarly prevalent. There is an urgent need to develop new tools for
structural biology and structure-function analysis of post-translational modifications. This
need is highlighted by a 2017 paper from the Showalter and Gilmour laboratories that
demonstrated phosphorylation of serine residues in the RNA Polymerase II CTD can
stimulate proline trans-to-cis conformational transitions in specific sequence contexts,
which can be read out by downstream enzymes. Motivated by this exciting discovery,
the Showalter laboratory seeks to develop spectroscopic methods that will allow
systematic exploration of structure-function relationships involving post-translational
modification. This work will be made possible with support from NSF grant MCB-

Dr. Showalter has received a new grant from the National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK) to explore how protein-protein interactions
regulate the activity of the pancreatic transcription factor Pdx1. In developed organisms,
Pdx1 expression is restricted to only a few cell types, most notably the β-cells of the
pancreatic islets of Langerhans. In the β-cell, Pdx1 is a necessary component of
transcription regulation for genes associated with endocrine pancreas function,
including insulin. Related to this function, Pdx1 mutations have been identified as
monogenic drivers of diabetic phenotypes. In development, Pdx1 expression contributes
to cell type differentiation that ultimately leads to formation of the pancreas. Related to
this developmental function, aberrant expression of Pdx1 has been associated with the
progression of some pancreatic cancers. With this new funding, the Showalter
laboratory will investigate down-regulation of Pdx1 by the E3 substrate adaptor protein
SPOP, and co-activation of Pdx1 via interactions with the methyltransferase Set7. This
work will advance fundamental understanding of gene regulation, while also contributing
new insights into the molecular basis of diabetes, and the etiology of adenocarcinomas with broad primary tissue distributions, but most notably in the pancreas. This work will
be made possible with support from NIH R01 grant DK121509.