Epigenomics Program
Despite recent dramatic advances in care, there are still patients who exhaust all conventional treatment options. Scientists working to help these patients use genomics to examine the differences between each patient's typical DNA and the disease-causing, atypical DNA. However, to pinpoint new molecular targets for therapy for these patients, researchers cannot stop there. They also must examine other factors that influence how genes are expressed.
These other factors are proteins that chemically modify the DNA without altering the genetic code and DNA-associated proteins that regulate gene transcription. Such gene modifiers and regulators are collectively known as epigenetic mechanisms, as they cause changes in genes above and beyond changes in the DNA sequence.
Epigenetic mechanisms can be passed on when cells divide, so they have a long-term influence on how cells behave and can contribute to the etiology and progression of diseases. Today, researchers can characterize the entire epigenomes of cells that are affected by disease, even though every patient has their own unique epigenome. This is possible by observing how epigenetic information for epigenetic regulators and chromatin structure is distributed across each patient's entire genome.
This capability, together with a rapidly increasing list of medicines that target epigenetic mechanisms, increases the possibility of using epigenomics more widely to personalize diagnostics and treatments. Better understanding epigenomics and related technologies and applying them to patient care is central to the work of the Epigenomics Program.
Projects
A research team led by Mrinal S. Patnaik, M.B.B.S., is studying clonal hematopoiesis. The team's goal is to understand the differences between specific mutations involved in competitive advantage for hematopoietic clonal expansion. Clonal hematopoiesis of indeterminate potential influence the mortality and morbidity of patients with COVID-19 due to exaggerated cytokine release syndromes, acute lung injury and multiorgan dysfunction syndrome.
A recent study focused on clonal hematopoiesis-putative driver genes as biomarkers for exaggerated inflammatory responses in patients with COVID-19.The research team used multi-omic integration of genomic, transcriptomic, epigenetic and proteomic analysis of patient samples. The study profiled 227 patients with moderate to severe COVID-19 and detected the presence of clonal hematopoiesis in 25% of patients.
The most common somatic mosaic states included mutations in the DNMT3A and TET2 genes. DNMT3A mutations were associated with increased severity of cytokine release and with the higher inflammatory morbidity. These gene changes also negatively impacted patients' overall rates of survival. TET2 mutations were associated with the expression of a novel, proinflammatory, long noncoding RNA called MALAT1.
Patients with chronic myeloid neoplasms such as chronic myelomonocytic leukemia frequently have changes in chromatin-remodeling proteins such as ASXL1. These changes alter protein function and lead to a profound dysregulation of gene expression. They also promote disease proliferation and resistance to the currently available epigenetic therapies. Such changes are associated with increased morbidity and mortality for patients.
A project led by Moritz Binder, M.D., M.P.H., aims to find new epigenetic therapeutic targets for patients who have chronic myelomonocytic leukemia with changes to ASXL1. The project investigates the role of genotype-specific distal enhancer elements in regulating the expression of important leukemogenic driver genes. To accomplish this, researchers combine high-throughput sequencing data from RNA-seq, ChIP-seq, DIP-seq, ATAC-seq and HiChIP, and use cutting-edge computational biology approaches.
The project focuses on identifying cis-regulatory interactions that cause cancer. Researchers are finding ways to use these interactions to improve treatments with new and unique epigenetic small-molecule therapeutics. A new small-molecule therapy has shown promise in preclinical models. Researchers are now developing an early-phase clinical trial for patients who have chronic myeloid neoplasms with changes to ASXL1.
The laboratory led by Alexandre Gaspar Maia, Ph.D., is studying transcription and enhancer regulation with implications in cellular heterogeneity and drug resistance in cancer and cellular reprogramming.
The lab's goal is to use epigenomic profiling to better understand cancer programs associated with malignancy, metastasis and drug sensitivity and define transcriptional dependencies. To achieve this long-term goal, the research team uses three complementary avenues:
- Technology development. Dr. Maia's team adapts the most recent advances in sequencing technologies to model systems such as 3D organoids, patient-derived xenografts and liquid biopsy. The goal is to address tumor heterogeneity and epigenomic profiling in small populations of cells.
- Bioinformatic analysis. Researchers focus on extracting the most information from RNA-seq, HiChIP, HiC, ATAC-seq and single cell ATAC-seq/RNA-seq data. The research team has a special interest in using machine learning to identify epigenomic patterns.
- Mechanistic studies. The research team uses CRISPR/Cas9-based technologies and coculturing systems to address cellular heterogeneity. The team targets new and unique transcription factor candidates and noncoding elements of the genome to functionally validate their roles in drug sensitivity. The lab tests different drug combinations by pairing a time-lapse culturing system, Incucyte, with advanced culturing systems using microfluidic devices.
A research team led by Tamas Ordog, M.D., is studying the basic and translational biology of the gastrointestinal tract's neuromuscular compartment. In particular, the team is focused on the epigenomics of enteric neurons, electrical pacemaker or neuromodulator cells, and related sarcomas.
Dr. Ordog's team uses cultured and freshly purified murine and human cells as well as genetically engineered murine models to investigate the function of cis-regulatory elements close to and far away from the genes in question. The team studies the interactions of these elements in space and time under physiological conditions. Researchers also observe responses to metabolic disturbances associated with human diseases, including diabetes and cancer.
When the team discovers epigenetic targets that can be controlled or influenced with drugs, researchers conduct additional experiments. In these experiments, they use preclinical animal models of complex diseases and cancer to test treatments that could potentially be translated to patient care.
Renal cell carcinoma, a type of kidney cancer, is one of the top 10 causes of cancer-related death. In primary and metastatic clear cell renal cell carcinoma, researchers have found loss-of-function variations in the epigenetic regulator SETD2, a histone H3 lysine 36 trimethyltransferase.
A project led by Keith D. Robertson, Ph.D., aims to find new treatment options for people with kidney cancer. Researchers are identifying gene networks in which regulation is disrupted by reduced histone H3 lysine 36 trimethylation.
Epigenomic neurodegenerative disease researchers at Mayo Clinic aim to bridge the gap between the genetic knowledge accumulated over the last three decades and patient care today. Research goals are to guide more tailored management of patients and to inform the next generation of individualized clinical trials. Research in this area is led by Nilufer Ertekin-Taner, M.D., whose laboratory studies the genetics and endophenotypes of Alzheimer’s disease.
Researchers create high-resolution profiling of genomic, epigenomic and transcriptional changes in various human tissues and fluids. Investigators carry out this multi-omic approach at three distinct levels of resolution: bulk, sorted nuclei and single cell. The goal is to develop and apply methods to identify disease-specific variants. From there, researchers can explain the variants' underlying mechanisms of action and shed light on distinct circuitry. Ultimately, researchers aim to identify static and dynamic biomarkers and find therapeutic targets for patients.
Neurodegenerative diseases are characterized by the progressive loss of brain cells. Finding biomarkers to facilitate early diagnosis, predict prognosis, stratify patients, identify surrogate endpoints and assess target engagement during clinical trials would be groundbreaking. Equally important, identifying therapeutic targets would drive the development of strategies to prevent, slow down or stop neuronal death in patients.
Mayo Clinic's Epigenomics Developmental Laboratory and Recharge Center recognizes this urgent need. The facility has implemented a biomarker and therapeutic target discovery platform for multiple neurological diseases to bring experimental findings quickly from the bench to the bedside.
In collaboration with Manolis Kellis, Ph.D., at the Massachusetts Institute of Technology and the Broad Institute, a Mayo Clinic team led by Tamas Ordog, M.D., researches psychiatric diseases. Specifically, the group studies whether multiparameter epigenomic profiling of circulating white blood cells can provide insights into the development of bipolar disorder. This includes investigating the involvement of immune dysregulation and genotype-phenotype interactions. The team also aims to identify hidden subsets of patients and the biomarkers for these disease subgroups. To identify these subsets, researchers combine peripheral epigenomic profiles with electronic health record data.
Mayo Clinic collaborators include Joanna M. Biernacka, Ph.D., Mark A. Frye, M.D., and investigators from the Mayo Clinic Biobank and the Epigenomics Development Laboratory and Recharge Center.
Methods and instrument development and recharge service
The Epigenomics Development Laboratory and Recharge Center provides collaborative and end-to-end epigenomic services to Mayo Clinic researchers and external investigators. Investigators need only send in their samples, and the facility staff does the rest, up to and including next-generation sequencing library preparation.
Educational initiatives
The Epigenomics Program has established and continues to develop a variety of educational opportunities related to basic and translational epigenomics for students, fellows, and clinical and basic investigators at Mayo Clinic's campuses in Arizona, Florida and Minnesota.
These opportunities include:
Mayo Clinic Center for Individualized Medicine Epigenomics Program
Mrinal S. Patnaik, M.B.B.S., the Epigenomics Program director, describes the services available to researchers through the Epigenomics Development Laboratory and Recharge Center.
Epigenomics Animation
Epigenomics investigates the role of the epigenome, which factors act on individual genes, and how certain changes in the epigenome affect personal health.