Genetic polymorphisms in chromatin regulators have been identified in chronic immune diseases such as asthma, inflammatory bowel disease (IBD), and systemic lupus erythematosus (SLE), and the functional consequences of these remain unknown. Our lab explores how genetic variants in chromatin regulators of innate immunity are drivers of complex immune disorders.      

a. Role of chromatin regulators in myeloid lineage integrity

    
Our lab investigates the molecular mechanisms by which chromatin regulators instruct myeloid lineage commitment during hematopoiesis. Our lab’s particular focus is on chromatin repressors and how genetic variants of granulopoiesis/myelopoiesis specific-chromatin repressors disrupt lineage integrity and serve as precursors for disease pathogenesis. 

b. Role of chromatin regulators in myeloid response

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Our lab investigates how chromatin regulators shape macrophage transcriptional responses and, importantly, how the inability to integrate environmental cues by disrupted chromatin readers is a sentinel event in complex immune disorders. We also assess the therapeutic tractability of targeting these enzymes in chronic inflammatory diseases.

Local micro-environmental cues (e.g., trace elements, hormones, metabolites, and gut microbiome) are essential for imprinting tissue-specific roles in the macrophages through regulation of unique enhancer landscapes and transcriptional programs.

Our lab studies how micro-environmental cues are integrated by the host chromatin to regulate homeostatic immunity. 

a. Role of chromatin in the integration of host-microbiome interactions

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‍Commensal microbiome play a critical role in the development and function of the host immune system. The molecular mechanisms by which this crosstalk occurs between the host and the diverse local microbiome to maintain immune homeostasis is an active area of investigation. Our lab explores how gut microbiome interactions are integrated by the innate immune chromatin to collectively shape host immune responses. 

b. Role of chromatin in the integration of fetal-maternal interactions

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‍Hofbauer cells are fetal-derived macrophages that reside at the fetal-maternal interface and are enriched in early pregnancy. Our lab is interested in understanding how these cells integrate complex environmental cues from the fetal-derived placenta and the maternal-derived decidua to maintain the health of both the fetus and the maternal host.

There is unequivocal evidence that climate change has led to increased and unpredictable exposures of our innate immune cells to novel or redistributed allergens, pathogens (parasites and fungi), anthropogenic pollutants, extreme weather patterns (forest fires), as well as stochastic combination of exposures; however, the consequences of these exposures on chronic human health remain poorly characterized. We study how exposure of innate immune cells to macro-environmental factors leads to changes in the chromatin landscape and alters immune outcomes.

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a. Role of environmental exposure induced-innate immune memory in chronic immune diseases

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Accumulating evidence demonstrates that innate immune cells possess “memory” of the environmental trigger, which can impart future functional consequences. This de facto memory from chromatin and metabolic reprogramming can lead to either enhanced (‘training’) or diminished (‘tolerance’) cytokine transcription following re-challenge. While this trained immunity may confer protection against heterologous infections, it is speculated as maladaptive in the context of chronic inflammatory diseases.

Our lab is interested in understanding how early exposures to air pollution, antibiotics, and allergens can lead to long-term chromatin changes to macrophage plasticity and homeostatic function and prime for future chronic immune disease. 

b. Environmental context-specific effects of genetic variants on immune responses

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‍We are interested in understanding how the local environment directly interacts with genetic factors. We are specifically asking how genetic variation, including less common non-coding variants, can modulate an individual’s immune response to specific environmental challenges.

There is a large gap in knowledge in our understanding of heterogeneity in clinical phenotypes (penetrance and disease expressivity) commonly observed in different patients with the same mutation. Our research questions aim to address whether disruption of chromatin regulator is sufficient for disease pathogenesis or requires environmental exposures as a “second hit” and whether a unique disease trajectory is driven by an environmental exposure at a critical developmental window.