Joshua Tompkins, Ph.D.

The Tompkins team represents a direct continuation of several core research projects initiated alongside Arthur Riggs, PhD., before his untimely passing in 2022. Major works include 1) epigenetic DNA methylation engineering, with special emphasis on stem cell and heritable forms of epigenome engineering, 2) detection and correction of epigenetic sites of long-term diabetes complications, 3) epigenomic mapping of pluripotent derived cell products, and 4) the use of innovative systemic aging interventions to mitigate diabetes complications. His team is studying how DNA methylation is correlated with cell fate, aging, diabetes and its complications, as is investigating strategies to reverse epigenetic events associated with these processes.

Aging and virtually all human diseases involve dysregulation of the epigenome. Our research involves fundamental inquiry into epigenetic features of diabetes, cancer, and cardiovascular disease, seeking to understand which intrinsic features are correlated with aging or disease progression, and which are therapeutically reversible.

Toward this goal, we are actively working on multiple interrelated projects spanning:

• The study of epigenetic “memories” and targeted reversal in long-term diabetes complications
• The development of techniques for programming heritable DNA methylation to model human epigenetic aging and disease
• The use of pluripotent stem cells and directed to differentiation to model diabetic disease and for cell replacement-based medicine
• The application of age-augmenting therapeutic blood exchanges to alleviate diabetic complications     

DNA Methylation Engineering and Directed Differentiation

DNA methylation enables development and functions as a known regulator of transcription and repetitive element activity. A covalent DNA modification that occurs predominately at cytosine, DNA methylation represents a highly specific disease- and age-specific biomarker. Its deposition unfolds with such remarkable predictability that several epigenetic “clocks” can now accurately predict the biological age of an individual based on specific patterns of CpG DNA methylation. Enzymatically written, DNA methylation is erased genome-wide between generations and in primordial germ cells and the early stages of pre-implantation development, enabling a genomic reset between parent and child. There is strong evidence that rare imprinting sites escape this erasure and influence embryonic development and future disease. There is also evidence that some environmentally induced DNA methylation changes are transgenerationally retained and influence human disease propensity across generations. To investigate and correct, we have developed techniques to pattern-stable, site-specific DNA methylation, faithfully programmed with each ensuing generation. Both in vitro and in vivo, CpG Island Methylation Responses (CIMRs) are specific genome-wide, enduring, influence cell fate, and specified de novo DNA methylation is heritable in virtually all tissues. As City of Hope is both a diabetes and cancer research center, designer DNA methylation targets epigenetic obesity, cardiovascular disease, and cancer murine model building and strategies to remove pathological sites of DNA methylation. We specialize in the dCas-based epigenetic editing tool development and the directed differentiation of multiple lineages for modeling and cell replacement medicine, with expertise in cardiomyocyte and thymic epithelial cell production.

Epigenetic Memories

Differentiation requires DNA methylation, and we have previously observed human pluripotent stem cell differentiation marked by dynamic changes to the epigenome and genome-wide DNA methylation. By mapping these epigenetic changes over time, we have uncovered several examples of epigenetic “memory,” in which transcriptional history is recorded onto DNA. In some cases, this may be functional, and in others, this may be pathological. For example, our collaborator Rama Natarajan, Ph.D., through a series of landmark studies, has identified that a period of poor glucose management can result in future long-term health complications, both microvascular and macrovascular, which involve multiple organ systems. Remarkably, health complications from type I diabetes may be predicted decades before their emergence by specific sites of DNA methylation change. As a functional recording of prior hyperglycemia, sites of “metabolic memory” are stably altered across the genome, and these accelerate an individual’s propensity to develop vascular disease, retinopathy, and nephropathy. Beyond biomarker detection, we are developing tools that enable the induction and erasure of pathological DNA methylation, with specialized delivery approaches to target specific types of pluripotent and multipotent stem cell populations capable of carrying DNA methylation edits through development. These approaches are aimed at functionally erasing novel and established biomarkers of diabetes complications.

Therapeutic Blood Exchanges

Since the first systemic plasma depletion experiments, and more contemporaneously through young-old murine parabiosis study, physicians and scientists have observed systemic benefits imparted by whole blood exchange and pheresis therapies. The latter is known to be particularly effective in alleviating severe autoimmune attacks and in treating familial hypercholesterol syndromes, blood cancers, neurological conditions, and kidney disease, among others. Yet, due to small blood vessels and the complexities of conducting blood exchanges in murine models, therapeutic blood exchange work in mice has been extremely limited. To overcome this hurdle, we have developed a semi-automated blood exchange approach for conducting therapeutic blood exchanges between aged and young mice. The approach imparts significant tissue regenerative benefits to aged recipient mice, including skeletal muscle, liver, and vascular improvements and the reduction of biological age by predictive DNA methylation patterning. Currently, we are using this model system to inform translational blood exchange interventions that may mitigate diabetes and its complications in humans, especially vascular complications, and to investigate the depletion of circulating small extracellular vesicles, which may drive disease.
Funding for these projects comes from a network of collaborators and core services at City of Hope and the Translational Genomics Research Institute, such as the generous support of Dr. Riggs and his family. The Wanek Family Project for Type 1 Diabetes at City of Hope and the Dorrance family project on extracellular vesicles at Translational Genomics offer partial support for research on metabolic memory and extracellular vesicles.

Learn more about the Tompkins Lab and related research at Epigenome Engineering.

Lab Alumni

Former Research Associates

• Elizabeth Lizhar, M.S.
• Swetha Godatha, M.S.
• Jordan Berley, M.S., PharmD
• Diba Kamali, M.S.
• Anand Upadhyaya, M.D.

Former Co-Mentored Students

• Jonas Cerneckis, B.S.
• Pratibha Mishra, Ph.D.
• Jonathon Wise, Ph.D.