(1) Functional Histone Genetic Experiments in a Mouse Model:
There exists a gap in our understanding of fundamental epigenetics in complex organisms. This is because most of what we know of histone function comes from elegant genetic experiments performed in model organisms that share a common ancestor with humans and mice more than 500 million years ago. In this work, we are developing tools to perform functional histone genetic experiments in mouse. The goal is to provide the capability to perform functional studies of histone genes and residues in vivo in a mammalian model system. Given our focus on the hematopoietic and immune systems, and their function, there is an exciting potential for this project to synergize with other work in the lab and for expanding these tools to study the role of histone residues in epigenetic features of immunity such as immunologic memory, immune cell exhaustion, “trained immunity” (see below), and more.
(2) Mechanisms and Function of Epigenetic Memory of Inflammation in Hematopoietic Stem Cells:
The term "trained immunity" indicates an organism's durable memory of inflammation that is independent of immunologic memory as mediated by adaptive immune cells. It has become clear that such memory can reside in the hematopoietic stem cell (HSC) compartment. The implications of such memory are remarkable and likely to feature in immunity, autoimmunity, and vaccine responses, but the mechanisms of transcriptional and epigenetic regulation of this "training" in HSCs are unknown. We explore these mechanisms and functional implications of “HSC training”, leveraging a specialized toolkit for working with HSC, functional histone genetic experiments, epigenomic assays (including HiC, small cell number ChIP). We are especially interested in investigating epigenetic “memory” of childhood inflammatory events and if these may contribute to pediatric inflammatory disease.
(3) “Signaling to Chromatin” Pathways in Immune Cell Development and Function:
We study how immune signaling events are transmitted to chromatin to selectively induce inflammatory genes in macrophages responding to inflammatory cues. These studies establish the cooperative role of epigenetic mechanisms (histone modifications) and transcription factor activity— both regulated by signaling kinases— highlighting the coordinated function of these factors. Our ongoing studies are revealing epigenetic mechanisms that have dedicated function in rapid stimulation-induced transcription, critical for immunity and coopted in cancer. Targeting such dedicated mechanisms that enable inflammatory gene (and oncogene) induction may provide more selective therapeutic strategies for diverse inflammatory diseases and cancer. A long term career goal is to apply mechanistic knowledge of epigenetic regulation of inflammation to better understand inflammatory disease, trained immunity, immune cell exhaustion, and other epigenetic immune phenomena.