Despite dramatic advances of disease treatments in recent years, there are still patients who exhaust all conventional treatment options. To pinpoint new molecular targets for therapy for these patients, scientists cannot stop at using genomics-based approaches to examine the differences between each patient's typical DNA and the disease-causing atypical DNA. They must also examine other factors that influence how genes are expressed.
These other factors are proteins that chemically modify either the DNA — without altering the genetic code — or DNA-associated proteins that regulate gene transcription. Such gene modifiers and regulators are collectively known as epigenetic mechanisms, as they cause gene variation 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 individual patients' diseased cells by monitoring the genome-wide distribution of epigenetic information for epigenetic regulators and chromatin structure.
This capability, together with a rapidly increasing list of compounds and drugs that target epigenetic mechanisms, is increasing the possibility of more widely using epigenomics 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.
Clonal hematopoiesis of indeterminate potential may have an influence on the mortality and morbidity of patients with COVID-19 as a result of exaggerated cytokine release syndromes, acute lung injury and multiorgan dysfunction syndrome. A research team led by Mrinal S. Patnaik, M.B.B.S.,is assessing the impact of clonal hematopoiesis-putative driver genes (CH-PD) as a biomarker for exaggerated inflammatory responses in patients with COVID-19, using multiomic integration of genomic, transcriptomic, epigenetic and proteomic analysis of patient samples.
The aims of this study are to determine the correlation between CH-PD and inflammatory responses in people with COVID-19 and to correlate the epigenetic impact of CH-PD on inflammatory outcomes.
A research team led by Tamas Ordog, M.D., is focused on basic and translational biology of the gastrointestinal tract's neuromuscular compartment, with particular attention to 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 gene-proximal and gene-distal cis-regulatory elements and their interactions in space and time under physiological conditions and in response to metabolic disturbances associated with human diseases, including diabetes and cancer.
Pharmacologically tractable epigenetic targets discovered in these experimental paradigms are further interrogated in preclinical animal models of complex diseases and cancer using agents with translational potential.
Led by Alexandre Gaspar Maia, Ph.D., Mayo Clinic's Laboratory of Functional Epigenomics, in collaboration with other groups, focuses 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. By adapting the most recent advances in sequencing technologies to model systems such as 3D organoids, patient-derived xenografts and liquid biopsy, researchers aim to address tumor heterogeneity and epigenomic profiling in small populations of cells.
- Bioinformatic analysis. The lab focuses on extracting the most information from RNA-seq, HiChIP, HiC, ATAC-seq and single cell ATAC-seq/RNA-seq data, with a special interest in incorporating machine learning to identify epigenomic patterns.
- Mechanistic studies. Using CRISPR/Cas9-based technologies and coculturing systems to address cellular heterogeneity, Dr. Maia's team aims to target novel transcription factor candidates and noncoding elements of the genome to functionally validate their roles in drug sensitivity. Coupling a time-lapse culturing system, Incucyte, with advanced culturing systems using microfluidic devices allows the lab to test different drug combinations.
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, loss-of-function variations have been found 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 by identifying gene networks dysregulated by reduced histone H3 lysine 36 trimethylation.
Epigenomic neurodegenerative disease researchers at Mayo Clinic aim to help bridge the gap between genetic knowledge accumulated over the last three decades and clinical presentation, to guide more tailored management of patients, and to inform the next generation of individualized clinical trials.
To do so, they generate high-resolution profiling of genomic, epigenomic and transcriptional alterations in various human tissues and fluids. Investigators carry out this multiomic 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, elucidate their underlying mechanism of action, shed light on distinct circuitry, and ultimately identify static and dynamic biomarkers and putative therapeutic targets for patients.
Mayo Clinic investigators taking epigenomic approaches to neurodegenerative disease research include:
Identification of biomarkers to facilitate early diagnosis, predict prognosis, stratify patients, identify surrogate endpoints and assess target engagement during clinical trials would be groundbreaking for neurodegenerative diseases, a group of disorders characterized by the progressive loss of brain cells. Equally important, identification of therapeutic targets would drive the development of strategies to prevent, decelerate or stop neuronal death in patients.
Mayo Clinic's Epigenomics Developmental Laboratory and Recharge Center recognizes this urgent need and has implemented a biomarker and therapeutic target discovery platform for multiple neurological disorders to bring experimental findings quickly from the bench to the bedside.
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, lead to a profound dysregulation of gene expression, promote disease proliferation and resistance to the currently available epigenetic therapies, and 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 with ASXL1-mutant chronic myelomonocytic leukemia. By integrating high-throughput sequencing data from RNA-seq, ChIP-seq, DIP-seq, ATAC-seq and HiChIP, and employing innovative computational biology approaches, the project investigates the role of genotype-specific distal enhancer elements in regulating the expression of important leukemogenic driver genes.
The project focuses on identifying oncogenic cis-regulatory interactions that may be exploited for therapeutic benefit with novel epigenetic small-molecule therapeutics in future early-phase clinical trials for patients with ASXL1-mutant chronic myeloid neoplasms.
Prostate cancer is one of the most common and lethal types of cancer. The SPOP gene, which encodes a substrate-binding adaptor of the Cullin-3-based RING box E3 ubiquitin ligase complex (CRL), is frequently altered in both primary and advanced prostate cancer. Notably, the genomic DNA in SPOP-altered prostate cancer is hypermethylated, but the underlying mechanism has long been unclear.
A recent study conducted in the laboratory of Haojie Huang, Ph.D., showed that a change in the SPOP gene results in aberrant stabilization of the histone methyltransferase complex GLP/G9a, which promotes DNA hypermethylation and silencing of an array of tumor suppressor genes by interacting with and recruiting the DNA methyltransferases into chromatin.
Dr. Huang's team also provided evidence suggesting that SPOP alteration could be a biomarker for targeted therapy of prostate cancer by combining DNA methylation inhibitors and chemotherapeutic agents.
- Zhang J, Gao K, Xie H, Wang D, Zhang P, Wei T, Yan Y, Pan Y, Ye W, Chen H, Shi Q, Li Y, Zhao SM, Hou X, Weroha SJ, Wang Y, Zhang J, Karnes RJ, He HH, Wang L, Wang C, Huang H. SPOP mutation induces DNA methylation via stabilizing GLP/G9a. Nature Communications. 2021; doi:10.1038/s41467-021-25951-3.
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.
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:
- Three courses offered in the biochemistry and molecular biology Ph.D. track and clinical and translational science Ph.D. track in Mayo Clinic Graduate School of Biomedical Sciences
- A seminar series featuring speakers from Mayo Clinic and other organizations
- Biweekly epigenomics journal club and bioinformatics journal club
- Web-based educational material
- Scholarly publications
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 investigates the role of the epigenome, which factors act on individual genes, and how certain changes in the epigenome affect personal health.