The Center for Epigenomics at
UC San Diego is pleased to lead academic investigator partnerships with our
Transformative Collaborative Pilot Project Initiative. The goal of this program is to stimulate groundbreaking collaborative research between San Diego investigators and the Center for Epigenomics. This research will use epigenomic concepts and technologies to make transformative discoveries which advance science and human health. Each year we issue a call for applications in the spring, and typically select three or more
collaborative projects; these projects are expected to lead to joint large-scale grant applications and publications. The Center for Epigenomics will commit up to
$100,000 in resources to each collaborative pilot project (in the form of epigenomic assays, reagents, personnel effort, etc.). In accordance with the collaborative nature of these projects, successful applicants will likewise be expected to commit considerable resources. The application phase is closed for 2019 but will open again early 2020.
Transformative Collaborative Pilot Projects 2019-2020
Developing single cell Patch ATAC Seq to understand the epigenetic basis of neuronal diversity in the mammalian central nervous system
PI: Dr. Binhai Zheng, UC San Diego
Abstract: Single cell technologies provide unprecedented opportunities to understand neuronal diversity that underlies the most complex system in our body, the central nervous system (CNS). To date, most single cell studies have focused on higher throughput pipelines with lower reads per sample that only enable broad categorization of neuronal types. Within each neuronal type, there are often multiple subtypes that possess different morphological, anatomical and physiological properties. Each neuronal subtype may exist in different states that respond to physiological and pathological challenges differently. To start to unravel this complexity, we are collaborating with the UCSD Center for Epigenomics to develop a single cell Patch ATAC Seq platform and use it in conjunction with single cell Patch RNA Seq to dissect higher level neuronal diversity. Our central hypothesis is that neuronal subtypes and their intrinsic states as defined by their epigenome and transcriptome are important determinants of their regenerative abilities after injury. While we focus on the biology of neuronal regeneration here, the same concept applies to other aspects of neuronal diversity such that the pipeline developed here will be applicable to studying a variety of nervous system conditions from Alzheimer’s to autism.
Elucidating the Changes in Epigenomic Landscape of Hepatic Stellate Cells During NASH Progression
PI: Dr. Debanjan Dhar, UC San Diego
Abstract: Non-alcoholic steatohepatitis (NASH) is a severe and chronic liver inflammation that predisposes a patient to end-stage liver disease (cirrhosis), liver failure and hepatocellular carcinoma (HCC). Hepatic fibrogenesis is a pathophysiological outcome of chronic liver injury hallmarked by excessive accumulation of extracellular matrix (ECM) proteins where hepatic stellate cells (HSCs) plays a central role. HSCs are the main ECM producing cells in the injured liver and are modulated by extracellular signals from resident and inflammatory cells including macrophages, hepatocytes, liver sinusoidal endothelial cells, and lymphocytes. Although much is known about signaling pathways that regulate HSC phenotype, the epigenetic mechanisms that regulate HSC activation and inactivation is poorly understood. In this “Transformative Collaborative Pilot Project”, we propose to elucidate the epigenetic landscape of activated and inactivated HSCs with the ultimate goal of uncovering novel therapeutic targets for NASH and fibrosis.
Interrogating regulatory consequences of protein-coding genetic variation
PIs: Dr. Alon Goren, Dr. Melissa Gymrek, UC San Diego
Abstract: Mutations in proteins inducing widespread transcriptomic changes are widely implicated in human disease. Intriguingly, different mutations in the same gene can result in distinct phenotypes ranging from no impact to severe health consequences. This project develops a high-throughput genome editing technique to simultaneously measure the regulatory impact of hundreds of protein-altering mutations in a particular DNA- or RNA-associated protein using single-cell RNA sequencing, with the ultimate goal of interpreting genetic changes leading to human disease.
Deciphering the Role of Microglia in Human Brain Development
PI: Dr. Nicole Coufal, UC San Diego
Abstract: Microglia are the resident macrophage of the brain and are increasingly recognized for their contribution to injury response and for their critical role in maintaining brain homeostasis. New evidence is emerging that microglia are essential for brain development, participating in synaptic pruning, secreting neurotropic factors, and clearing apoptotic cells, which all strongly influence neurogenesis. Despite the progress made in discerning microglia function in brain development, there is a dearth of information about human fetal microglia, from their transcriptomic heterogeneity to their gene regulatory networks during brain development However, due to drastic changes in the brain tissue environment during embryonic, postnatal, and adult stages, it is without doubt that the microglia transcriptome and regulome also differs greatly between those periods. In this Transformative Collaborative Pilot Project we will define the heterogeneity of the microglial transcriptome and chromatin landscape during human fetal development and identify novel microglial functions that may increase our understanding of the contribution of microglial to neurodevelopmental and neuropsychiatric diseases such as autism and schizophrenia.
Transformative Collaborative Pilot Projects 2018-2019
Dissecting the molecular mechanisms of human cortical oscillation with brain organoids
Collaborators(s): Dr. Alysson Muotri, UC San Diego
Abstract: Structural and transcriptional changes during early brain maturation follow fixed developmental programs defined by genetics. However, the physiological mechanisms leading to the emergence of an active neural network are not well understood, primarily due to experimental inaccessibility of the initial stages of the living human brain. The Muotri lab has developed cortical organoids that spontaneously exhibit periodic and highly regular oscillatory network events, followed by a transition to irregular and spatiotemporally complex patterns. The network activity exhibited by these organoids closely mimics features of late-stage preterm infant electroencephalography. In this transformative collaborative pilot project, The Muotri lab is working with the Center for Epigenomics to determine the epigenetic changes that occur during normal human brain development using functionally-active organoids, to determine how chromatin modifiers affect human brain oscillations. Picture from Cleber Trujilo, Alysson Muotri
Understanding how clonal hematopoiesis mediates cardiovascular risk through single cell transcriptome and epigenome analysis of clonal immune cells
PIs: Dr. Sotirios "Sam" Tsimikas, Dr. Rafael Bejar, Dr. Christopher Glass, UC San Diego
Abstract: Clonal hematopoiesis, a relatively common phenomenon in the population, affecting 10-20% of individuals by their eighth decade, resulting from somatic mutations driving clonal expansion of immune cells and mosaicism. While there is a small increased risk of hematologic malignancy due to clonal hematopoiesis, the increased mortality in these patients was surprisingly due to cardiovascular disease and not due to cancer. Furthermore, the risk of incident cardiovascular disease in individuals with clonal hematopoiesis is comparable or higher than that associated with traditional risk factors. The common mutations associated with clonal hematopoiesis affect epigenetic regulators, providing a clue that epigenetic and transcriptomic changes in clonal immune cells may be responsible for the cardiovascular risk. In this Transformative Collaborative Pilot Project, we utilize single cell transcriptome and epigenome analysis of mosaic individuals with coronary artery disease for comparative analysis of clonal versus non-clonal immune cells. Our findings have the potential to define the mechanisms of clonal hematopoiesis mediated cardiovascular disease, to identify predictors for those who will develop the disease, and to identify targetable pathways for effective risk modification.
Targeting Immune Super Enhancer Networks in Pancreatic Tumor
Collaborator(s): Dr. Ron Evans, Salk
Abstract. Tumors were first described as "wounds that do not heal" more than 40 years ago, highlighting similarities between normal wound repair and the chronic inflammation and tissue remodeling that underlies tumor growth. This sustained wound healing response is known to abnormally skew the recruitment, differentiation, and function of stromal cell populations, including immune cells, fibroblasts, and endothelial cells, towards a tumor-supportive role. However, the underlying epigenomic and transcriptional programs that dictate altered stromal cell function have not been well characterized. Moreover, it is unknown how aberrant epigenomic states within the stroma contribute to the poor therapeutic responses seen in inherently refractory cancers, such as pancreatic ductal adenocarcinoma. In this collaborative project between the Evans lab and the Center for Epigenomics, we employ cutting-edge single-cell genomic technologies to investigate these outstanding questions and explore how epigenome-targeted drugs rewire the tumor microenvironment. Collectively, this work will provide unprecedented insight into the epigenetic programs governing intra-tumoral stromal cell function and determine the therapeutic potential of targeting these pathways.