Investigating the role of epigenetic regulation in human health and disease
Recently, we held our Single Cell Epigenomics Scientific Challenge, where researchers submitted proposals for a single cell chromatin accessibility experiment. Now, we congratulate our three winners: Linda Smit, PhD, of VUmc Cancer Center Amsterdam, Carolina Soriano-Tarraga, PhD, of Washington University in St. Louis, and Koji Taniguchi, MD, PhD, of Keio University School of Medicine. From the mechanisms of cancer therapy resistance to the drivers of Alzheimer’s disease to the basis of inflammatory memory, find out what epigenetic insights they plan to uncover with the Chromium Single Cell ATAC Solution.
Scientists across the world are committed to uncovering the epigenetic regulators influencing crucial areas of human biology and disease. Moreover, they are looking to gain deep insights into how epigenetic regulation operates within the fundamental unit of biology: single cells. We saw evidence of this in the abstracts that were submitted for our Single Cell Epigenomics Scientific Challenge, in partnership with Active Motif. Thank you to the hundreds of researchers who sent in proposals detailing how you would use a single cell chromatin accessibility experiment to advance our knowledge of complex biology and human health.
As we reviewed each proposal, three stood out to us as demonstrating unique and critical applications of Chromium Single Cell ATAC (Assay for Transposase Accessible Chromatin). We’d like to highlight the innovative research of our three challenge winners, Linda Smit, PhD, of VUmc Cancer Center Amsterdam, Carolina Soriano-Tarraga, PhD, of Washington University in St. Louis, and Koji Taniguchi, MD, PhD, of Keio University School of Medicine. In the sections below, explore what motivates their work, and what they plan to uncover about the role of epigenetic regulation in human disease.
Defining the role of epigenetic factors in leukemia relapse
Dr. Linda Smit, principal investigator and group leader in the Department of Hematology at the VUmc Cancer Center Amsterdam, wants to understand why the benefits of most cancer therapies just don’t seem to last. Dr. Smit and her research team study acute myeloid leukemia (AML), a cancer characterized by accumulation of leukemic blasts in a patient’s bone marrow. Traditionally, AML is treated by chemotherapy. While therapy can hold off the cancer for a long time, Dr. Smit noted that AML patients have a high chance of relapse, with only 10–40% surviving beyond 5 years.
One reason for this poor treatment outcome is that a small population of chemotherapy-resistant leukemia cells, called minimal residual disease (MRD), still lingers in the body after therapy. Dr. Smit believes that MRD, a result of intra-tumoral heterogeneity in the treatment response, must be fully characterized, at the resolution of single cells, in order to understand why it resists chemotherapy and what cell populations within MRD contribute to relapse. Moreover, Dr. Smit’s research team recently discovered that targeting an epigenetic modifier can reverse chemotherapy resistance in MRD, suggesting that resistance may be driven by epigenetic mechanisms. This discovery led them to the idea that the Chromium Single Cell ATAC Solution could reveal important characteristics of AML MRD cells that contribute to the development of relapse.
We asked Dr. Smit what technology her team used previously to answer their questions about AML, and why they are excited to use Chromium Single Cell ATAC:
“Previously, we had been using flow cytometry detection of leukemia-specific membrane molecules and detection of genetic variants to identify and measure AML MRD. However, intrinsic refractoriness of MRD can be heterogeneous and largely caused by epigenetic mechanisms. We are therefore excited to use single cell ATAC (Assay for Transposase Accessible Chromatin) sequencing to elucidate the heterogeneity and regulatory landscape of MRD, and to provide insights into chromatin accessibility, transcription factor binding, and gene regulation in AML MRD cells. The results obtained will lead to future research investigating the contribution of the identified epigenetic mechanisms to MRD development in the individual AML patient, but will also guide research studying the efficiency of combination therapies to eliminate MRD and prevent relapse.”
We are very proud to support this important research and look forward to the insights on AML treatment strategies that Dr. Smit’s team will uncover using single cell ATAC sequencing.
Linking Alzheimer’s disease pathology and epigenetic factors
Dr. Carolina Soriano-Tarraga wants to understand the epigenetics of aging. A faculty member in the NeuroGenomics and Informatics group in the Department of Psychiatry at Washington University in St. Louis, her research focuses on epigenetic, genetic, and multiomic approaches to identify the causes of age-related diseases, including stroke and Alzheimer’s disease.
We asked Dr. Soriano-Tarraga what inspired her to pursue this area of research:
“I am fascinated by how epigenetic mechanisms might modulate gene expression as a consequence of micro/environmental exposures, working as an environmental mediator. I am also interested in how epigenetics may be one of the mechanisms involved in keeping the ‘metabolic memory’ of the body.”
Dr. Soriano-Tarraga’s next proposed project aims to uncover the epigenetic factors that can influence gene expression patterns associated with Alzheimer’s disease (AD). Dr. Soriano-Tarraga noted that AD is a complex, multifactorial neurodegenerative disorder, marked by, like many complex or inheritable disease traits, dysregulation at distinct omic layers, including the transcriptome and the epigenome. This has led her team to take an integrative approach to studying the disease. She said: “To achieve my objectives, I regularly combine tools: large and well characterized human cohorts, next generation sequencing (e.g. GWAS, EWAS, exome sequencing, single cell RNA-seq), bioinformatics, biostatistics, and omic-data integration.”
Recently, her team generated single nucleus RNA sequencing data from 68 human brain samples, from subjects with both late-onset and Autosomal Dominant AD (ADAD). They identified a subset of microglia that are present only in ADAD brains, further distinguished by significant differential expression for three genes (MECP2, SIN3A, CDKL5) associated with DNA remodeling and epigenetic mechanisms. Knowing the neuroinflammatory role microglia play in AD, they concluded that there may be epigenetic factors influencing microglial behavior in the diseased brain. Now, Dr. Soriano-Tarraga and her team want to fully characterize the epigenetic factors associated with AD etiology, and they plan to use the Chromium Single Cell ATAC Solution, integrated with their single nucleus RNA-seq data, to reach those insights.
Dr. Soriano-Tarraga is excited to use Chromium Single Cell ATAC, a new addition to her research toolkit. We asked her why and how she thought this solution could change her research:
“I will be able to analyze thousands of brain nuclei at single cell resolution. I will be able to study accurate epigenomic profiling of different cell types and states… Moreover, completion of this project will provide an enhanced characterization of the epigenetic factors associated with AD etiology. This project will enhance our understanding of the molecular dynamics underlying the pathophysiology of AD, and may lead to novel clues for its early detection, prevention, and treatment.”
Exploring the epigenetic basis of inflammatory memory
It’s not just immune cells that retain cellular memory for inflammation and infection. Recent studies of human skin suggest that epithelial stem cells can also memorize the inflammatory response, and react quickly to the same inflammatory stimulus for several months. This phenomenon fascinates Dr. Koji Taniguchi, Associate Professor in the Department of Microbiology and Immunology at Keio University School of Medicine. Moreover, he’s interested in the role epigenetic modifications may play in establishing inflammatory memory in unexpected cell types.
Dr. Taniguchi’s focus is now on the inflammatory memory of the intestine, another epithelial-lined organ that serves as a protective barrier between the body and the outside world, much like the skin. His team has been able to identify some signaling pathways and transcriptional factors that may play a role in intestinal inflammatory memory, but are looking to gain deeper insights. We asked Dr. Taniguchi about the next steps for his study, and how he would like to use the Chromium Single Cell ATAC Solution:
“I am examining the intestinal inflammatory memory phenomenon in vivo and in vitro with the aim to elucidate its significance and mechanism. We can get more detailed information from each cell population by trying single cell ATAC-seq… We hope that we can identify what kind of epigenetic change occurs in each cell population during inflammation-related intestinal regeneration, and apply the new finding for treatment of patients with inflammatory bowel diseases and colorectal cancer."
Dr. Taniguchi and his team plan to integrate single cell ATAC-seq and single cell RNA-seq analysis to elucidate even more detailed mechanisms of inflammatory memory in the intestine. It’s an exciting proposal, and one that opens the door to further investigation into the role of epigenetic regulation in many more unexpected places in the human body.
Once again, congratulations to our three winners of the Single Cell Epigenomics Scientific Challenge! We can’t wait to see what you will uncover about epigenetic regulation.
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