Or P. Gozani
Virtually every cell in the human body contains the exact same DNA sequence. Yet these cells are dedicated to extraordinarily different functions. Some, such as stem cells, can divide rapidly and differentiate to regenerate a variety of cell types, whereas brain and heart cells, for example, are fixed in solid tissues and do not divide. How do these differences in cell types arise without alterations in the DNA sequence? How do stem cells know how to differentiate into one type of cell versus another? Our lab investigates these questions at the molecular level. Nuclear DNA is packaged and condensed by proteins and other factors into a highly dynamic structure termed chromatin. The marking of proteins present within chromatin by distinct chemical moieties is now appreciated to encode biological information that, while reversible, can be inherited from one generation of cells, and even organisms, to the next. Remarkably, this Eepigenetic inheritanceD occurs without a change in the sequence of the DNA. As a result, in contrast to DNA mutations in diseases (such as cancer) that are highly refractory to curative intervention, epigenetic alterations are reversible, and thus hold great potential as therapeutic targets. The goal of our research is to elucidate the molecular activities that translate chromatin modifications to biological functions, and to understand how disruption in these activities can trigger a pathologic state. The hope is that our research will lead to the discovery of novel strategies to improve upon current cures for cancer and other diseases. Specific areas of research include:
(1) The biology of chromatin modification: A central focus of my research group aims to understand the fundamental molecular mechanisms by which chromatin modification signals are sensed and transduced to effect diverse nuclear processes. A critical feature of any such pathway is the existence of protein modules present within chromatin-regulatory factors that function by selectively recognizing specifically marked histone species. We have discovered that a signature chromatin-associated protein motif, the PHD finger (Plant Homeodomain), is a novel chromatin effector domain. Specifically, we have found that the PHD finger of the tumor suppressor protein ING2 is a highly robust and specific binding module for histone H3 trimethylated at lysine 4 (H3K4me3). This study established a novel and pivotal role for H3K4me3 in acute gene repression, and as a ligand of ING2, tumor suppressor functions. Future research will expand upon these studies as well as explore the biological activities and pathways regulated by additional chromatin effector domains and their relationship to human health and disease.
(2) Lysine methylation signaling: modulation of protein-protein interactions: In addition to histone proteins, several other proteins undergo lysine methylation, suggesting that this modification may be a common mechanism for modulating protein-protein interactions and signaling pathways. My lab plans to identify and explore the biological and chromatin functions of diverse methylation events. We are utilizing biochemical and proteomic strategies to purify and identify novel methylated proteins, and pursuing the functional characterization of these methylated protein species utilizing an established paradigm developed in the lab.
(3) Nuclear phosphoinositide signaling: Phosphoinositides (PtdInsPs) are lipid molecules that play key roles in diverse signaling pathways. While much work has focused on PtdInsPs modulation of cytoplasmic processes, the role of PtdInsPs in the nucleus has been little explored. My lab is investigating the hypothesis that PtdInsPs regulate subnuclear trafficking of ING2 chromatin-regulatory complexes. We are also working to elucidate novel chromatin regulatory functions and molecular targets of nuclear PtdInsPs.
Ellison Medical Foundation Senior Scholar Award in Aging
David Huntington Dean’s Faculty Scholar