Despite dramatic advances in cancer therapies in recent years, there are still patients who exhaust all conventional treatment options. For these patients, pinpointing new molecular targets for therapy requires that we examine not only the differences between their "normal" DNA and the mutated DNA of their tumor, but also 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 contribute to the development of cancer and other diseases. Today, we can characterize the entire epigenomes of diseased cells from individual patients by monitoring the genome-wide distribution of epigenetic marks, along with their "writers," "readers" and "erasers."
This capability, together with a rapidly increasing list of compounds and drugs that target epigenetic mechanisms, is moving us closer to more widely using epigenomics for personalizing both diagnostics and treatments. Better understanding epigenomics and related technologies and applying them to patient care is central to the work of the Epigenomics Program.
Through a collaboration with the Pharmacogenomics Program, we facilitate the use of epigenomic technology in patients enrolled in the Breast Cancer Genome-Guided Therapy (BEAUTY) study.
Cancers with Mutations in Covalently Modifiable Histone Tail Residues
In some rare cancers – such as chondroblastoma and the pediatric high-grade gliomas diffuse intrinsic pontine glioma (DIPG) and glioblastoma multiforme (GBM) – mutations have recently been identified that interfere with the establishment and functioning of the so-called “histone code,” the body of covalent modifications of specific amino acids of histone proteins that govern key aspects of epigenetic control of gene expression. Work by investigators has revealed a complex set of epigenomic changes resulting from these mutations. Ongoing projects aim to better understand the molecular pathogenesis of the cancers carrying these mutations and identify potential therapeutic targets.
Alzheimer's disease, which today affects about 5.4 million people in the U.S., is a rapidly escalating epidemic. There is a pressing need to create treatments for Alzheimer's disease, but progress is limited by our lack of knowledge about the molecular pathways that affect someone's risk of developing the disease.
This project investigates the hypothesis that gene expression changes in the brain play a central role in a person's susceptibility to Alzheimer's disease, these changes are due to altered DNA methylation, and surveying methylated gene promoters can identify novel "druggable targets" for this disease.
There is not a routine test today that can detect endometrial cancer at an early stage. Such a test would vastly increase the chances of a cure in the more than 40,000 women diagnosed each year with endometrial cancer, the most common gynecologic malignancy in the U.S.
This project will identify novel biomarkers for early diagnosis of endometrial cancer by detecting hypermethylated gene promoter DNA in endometrial samples collected with the aid of the Tao Brush.
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 mutations have been found in the epigenetic regulator SETD2, a histone H3 lysine 36 trimethyltransferase.
This project aims to find new treatment options for people with kidney cancer by identifying gene networks dysregulated by reduced histone H3 lysine 36 trimethylation.
About 1 percent of people with an asymptomatic condition called monoclonal gammopathy of undetermined significance go on to develop multiple myeloma, an incurable plasma cell cancer with a median survival time of only three to four years. Genetic mutations account for the progression of monoclonal gammopathy of undetermined significance into multiple myeloma in some patients, but not all.
This project will identify multiple myeloma subtype-specific DNA methylation signatures to reconstruct the road map of disease development and progression, and ultimately identify new therapeutic targets for people with multiple myeloma.
Mutations in the gene encoding DNA methyltransferase 1 (DNMT1), the fundamental methylation enzyme essential in methylation maintenance during DNA replication and repair, cause sensory neuropathy with hearing loss and early-onset dementia. This hereditary disease involves both central and peripheral neurodegeneration.
To gain insight into the pathogenic mechanism of neurodegeneration, this project is examining genome-wide DNA methylation with single-base resolution along with genome-wide gene transcription analysis between four pairs of affected and unaffected siblings matched for sex and age.
Osteoarthritis is the most common form of arthritis and a leading cause of disability, but the molecular mechanisms of disease progression are poorly understood. Preliminary studies have indicated reduced DNA methylation and consequent increased expression of an osteoarthritis disease gene in undamaged cartilages of osteoarthritis patients.
The project's goal is to identify further hypomethylated genes that could serve both as biomarkers of osteoarthritis progression and new therapeutic targets.
Aging is associated with reduced reparative capacity in mesenchymal tissues, including bone, leading to impaired healing following injury and systemic diseases such as osteoporosis.
The isolation and characterization of highly enriched human osteoprogenitor cells obtained by depletion of bone marrow cells of all hematopoietic and endothelial cells and precursors has opened the door to detailed characterization of these cells in aging.
This project aims to describe age-related changes in gene expression and DNA methylation in freshly isolated osteoprogenitor cells in order to better understand the underlying biological processes and identify potential therapeutic targets.
Prostate cancer is the most commonly diagnosed cancer in U.S. men. In a subset of these men, loss of responsiveness to androgen withdrawal leads to disease progression and death.
One project in the Epigenomics Program is studying whether irregular expression of long noncoding RNA species could underlie silencing of tumor suppressor genes in therapy-resistant prostate cancer by recruiting the epigenetic silencer EZH2 to gene promoters.
Another project, which is being conducted in collaboration with the Pharmacogenomics Program, is investigating the hypothesis that in therapy-resistant prostate cancer, aberrant production of enhancer-derived noncoding RNA species may cause autonomous expression of androgen receptor target genes even in the absence of androgens.
Preeclampsia, a pregnancy-specific disorder involving maternal immune system dysfunction, occurs in approximately 5 percent of pregnancies and is a leading cause of both maternal and fetal morbidity and mortality. Genetic studies have so far failed to identify significant genetic variants underlying this heritable disorder.
This study aims to identify novel epigenetic biomarkers and potential therapeutic targets by profiling longitudinal changes in DNA methylation in maternal white blood cells (leukocytes) during preeclamptic pregnancies.
Methods and Instrument Development and Recharge Service
Chromatin immunoprecipitation sequencing (ChIP-seq) has become the method of choice for detecting the interactions between specific histone and nonhistone proteins, specific genomic sequences, and noncoding RNA. The related techniques, MeDIP-seq and hMeDIP-seq, detect genome-wide distribution of methylated and hydroxymethylated cytosine-DNA, respectively.
These techniques have significantly increased our understanding of the molecular mechanisms underlying epigenetic control and chromatin dynamics, and hold promise for providing unprecedented insight into disease processes in individual patients.
But in their standard form, ChIP-seq and (h)MeDIP-seq have major limitations, such as the requirement of large cell populations for input — preventing its application for small biopsy samples or rare cell types — and lengthy, complicated procedures that make routine use difficult.
The Epigenomics Program has established and validated standard ChIP-seq protocols for several histone marks, epigenetic regulators and transcription factors; and optimized them for use in archived, fresh-frozen patient samples. We also have developed and validated (h)MeDIP-seq using monoclonal antibodies developed in-house. These techniques and ChIP-PCR targeting specific genomic loci are now offered to Mayo Clinic investigators through the Epigenomics Recharge Center. Ongoing development targets the optimization of these methods for small patient samples and the expansion of the current method portfolio to include histone code “readers,” “writers” and “erasers,” as well as techniques to assess three-dimensional chromatin configuration.
A second project, which is being conducted jointly with the Department of Chemistry at the University of Illinois at Urbana-Champaign, will develop a new platform for analyzing protein-nucleic acid interactions that will permit automated, parallel analysis of multiple protein targets in samples consisting of very few whole cells or microliter volumes of human biopsy material.
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 Minnesota, Florida and Arizona.
These opportunities include:
- Three formal courses offered in the biochemistry and molecular biology track and clinical and translational science track in Mayo Graduate School
- An annual workshop as part of the Individualizing Medicine Conference that features world-renowed extramural speakers
- A seminar series featuring speakers from Mayo Clinic and other organizations
- Web-based educational material
- Scholarly publications
Tamas Ordog, M.D. Director
Grzegorz S. Nowakowski, M.D. Associate Director