Hye Kyung Lee, Ph.D.

Research Goal

The purpose of my studies is to unravel the genetic mechanisms governing the genome and to understand the impact of single nucleotide polymorphisms (SNPs) within the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway, which is implicated in cancer, developmental disorders, and autoimmune diseases. This knowledge will inform the development of targeted therapeutic strategies.

Current Research

My research focuses on understanding the regulation of common and cell-specific genetic programs controlled by cytokine-JAK/STAT signaling in development, immune homeostasis, and multiple autoimmune syndrome (MAS). It centers on three main aims:

1. investigating the roles of JAK/STAT SNPs identified in immune disorders and cancer,
2. examining the regulation of genetic programs by JAK/STAT SNPs using primary patient material,
3. inquiring about altered physiology and mechanism regulated by oncogenic STAT5 mutations identified in T-cell prolymphocytic leukemia, which were introduced into the mouse genome.

The first and last aims are primarily initiated and driven by my lab, while the second one is co-driven in a collaborative nature with community-based physicians and their patients.

Past Research

Cytokine-regulated Genes and Super-enhancers

Cytokines regulate the genome by activating the Janus kinases (JAK)/Signal Transducers and Activators of Transcription (STAT) signaling pathway. STAT5, a pivotal member of the STAT family, is crucial in cell lineages dependent on various cytokines. Our research have focused on mammary-specific enhancers and super-enhancers, elucidating their roles in regulating genetic programs during pregnancy and lactation. Investigating two distinct genetic loci using mouse genetics and genome-wide technologies, we have explored enhancer functions. Specifically, we have studied the 300 kbp casein locus containing multiple genes subject to diverse regulation and the Wap locus, which activates a single gene significantly during pregnancy. Using CRISPR/Cas9 genome editing and deaminase base editing, we investigated mutations' effects on enhancers during pregnancy and lactation. These studies deepen our understanding of mammary tissue genetic programs controlled by tissue-specific enhancers and super-enhancers via prolactin and the JAK/STAT pathway, revealing a novel hierarchy of regulation within enhancer clusters.

COVID-19 Pathology and Vaccination

Amid the onset of the pandemic in March 2020, I applied my expertise in cytokine-JAK/STAT signaling to COVID-19 research, focusing on the hyperinflammatory immune response characteristic of the disease. Initial investigations centered on understanding ACE2 expression regulation by interferons in human airway cells, highlighting the pivotal role of cytokines in SARS-CoV-2 target cells. Additionally, I explored the effects of JAK inhibitors, baricitinib and ruxolitinib, on interferon-activated ACE2 expression, relevant for therapeutic interventions. Subsequent studies delved into the impact of fast-spreading variants Alpha, Beta, Gamma, and Omicron, as well as prior vaccination on the innate immune response. Longitudinal transcriptome analyses revealed an active JAK-STAT-mediated immune response early in infection, persisting post-infection and following vaccination, with implications for boosting SARS-CoV-2-specific IgG and neutralizing antibodies. These findings provide valuable insights into the distinct molecular immune responses triggered by SARS-CoV-2 variants and vaccination across the course of COVID-19.

Genome Engineering

My research primarily revolves around experimental mouse genetics, wherein we have made significant contributions to refining relevant technologies. Specifically, our work has led to the discovery of aberrant chromosomal changes in CRISPR/Cas9-edited mouse genomes and the identification of compromised targeting fidelity in certain deaminase base editors. With extensive experience in genome editing techniques, particularly in introducing point mutations into the genome, our laboratory has utilized CRISPR/Cas9 and deaminase base editing to introduce single nucleotide variants (SNVs) into the mouse genome. These efforts have been instrumental in investigating the regulatory role of super-enhancers in genetic programs. Furthermore, we have introduced human missense mutations associated with cancer and autoimmune diseases into the mouse genome, specifically targeting the transcription factors STAT3 and STAT5B.

Research in Plain Language

Cytokines play a pivotal role in regulating various aspects of our physiological functions and can lead to diseases if their balance is disturbed. Our investigation primarily delves into interferons and interleukins, pivotal in maintaining the immune system's equilibrium and combating infections. Additionally, I explore how prolactin, a cytokine, influences mammary gland development during pregnancy and lactation, crucial for milk production.

Both immune cells and mammary glands are regulated by specific proteins known as JAKs and STATs. These proteins convey signals from cytokines bound to cell surfaces to the nucleus, activating precise genetic programs. I have also pinpointed mutations that disrupt the structure and function of JAK and STAT proteins, consequently affecting immune and mammary cell physiology, often resulting in severe repercussions.

Our research methodology encompasses a spectrum of disciplines, including biochemistry, genomics, genetics, and computational sciences such as machine learning and AI. In our exploration of immune disorders, including autoimmune conditions, we collaborate closely with community physicians and their patients.