Research Interests of the Center for Genomics

There are a few research interests and focuses in the Center for Genomics and Wang Lab.

1. Direct regeneration of cardiomyocytes from human blood cells and the epigenetics mechanism during the cell reprogramming: cardiac cell reprogramming and cell-based therapies are still far from a clinical practice, with much less satisfied outcomes in clinical trials. Particularly, one major concern of the current iPSC-based therapy is the possible formation of teratomas due to the viral integrations into the human genome and tumorigenesis of the residual undifferentiated iPSCs. Thus, there is an urgent need to develop a better method of cell reprogramming into heart cells. One major goal of this research effort is to develop a novel non-integrating method of directly converting human blood cells into heart cells using a set of combined factors. The second goal of the study is to investigate the single-cell epigenomic and transcriptomic landscapes of the direct conversion of human blood cells into heart cells. This study involves in the cutting-edge single-cell sequencing and CRISPR-Cas9 technologies.

2. FDA SEQC-2 multi-center cross-platform single-cell RNA sequencing comparison using reference samples: Single-cell RNA sequencing (scRNA-seq) has become a very powerful and affordable technology for biomedical research, but it is unknown how reproducible different platforms are using different bioinformatics pipelines particularly the recently developed new scRNA-seq batch correction algorithms. Under the FDA Sequencing Quality Control-2 (SEQC-2) consortium umbrella and in the collaborating with scientists from FDA, NIH/NCI and other industrial and academic organizations, the goal of this study is to carry out a comprehensive multi-center cross-platform comparison on different scRNA-seq platforms using standard reference samples, in which a large amount of whole epigenomic data was also available to help validate the scRNA-seq data. We compare six pre-processing pipelines, 7 bioinformatics normalizations and 6 batch effect correction methods to evaluate the performance and reproducibility of scRNA-seq across 7 data sets from 4 different platforms. We benchmark scRNA-seq performances across different platforms and testing sites using both global gene expression profiles as well as some cell-type specific marker genes including ones which are validated by both DNA methylation and chromatin accessibility by ATAC-seq. Our large cross-platform/site scRNA-seq data and findings will be great resources and guideline for the single-cell sequencing study community.

3. Spatial epigenetic single-cell atlas of human liver: The liver is the largest vital internal organ in humans. Liver diseases, in particular conditions such as drug-induced toxicity, alcohol-induced liver disease, cirrhosis, virus-induced hepatitis, and cancer, are pressing health concerns around the world. Each cell has a unique transcriptome that reflects the expression of a subset of genes, which can be affected by epigenomic stage or cellular microenvironment. Currently, there is no single-cell epigenomic atlas for human liver cells. The goal of this study is to construct a spatial 3D epigenetic single-cell atlas for human liver cells including single-cell transcriptomic and epigenomic data derived from both male and female livers to evaluate liver cell heterogeneity and their cellular functions. This study involves in scRNA-seq, scATAC-seq, scRRBS etc technologies.

4. Gene network alteration and pancreatic cancer progression affected by HPK1 gene in mouse pancreatic cancer cell lines, transgenic mice and patient samples: Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy, and the third most lethal among all cancers. Heterogeneity and immunosuppressive nature of tumor microenvironment are believed to be the major reasons for lacking of effective treatment. Recent studies demonstrated that a loss of hematopoietic progenitor kinase I (HPK1) correlates with PDAC progression and tumor immunosuppressive state. Repression of HPK1 is accompanied by up-regulation of oncogene Axl in PDAC. While it is known that the expression of Axl promotes immunosuppressive phenotypes in tumor microenvironment, the detail molecular mechanism of how HPK1 loss is promoting the pancreatic cancer progression is not completely known. Using systems biology approach, the goal of this study is to gain a comprehensive perspective on the immune landscape of pancreatic cancer as well as the roles HPK1 in pancreatic cancer immune suppressive state possibly through interaction with Axl in the context of tumor microenvironment. This study exploited the state-of-art single-cell and bulk cell sequencing at epigenomic and transcriptomic levels utilizing KO mouse pancreatic cancer cell lines, transgenic mice and human pancreatic cancer tissues. This study is in collaborating with Dr. Hua Wang at MD Anderson Cancer Center.

5. Epigenomics and longevity/health: What determines lifespan in humans? Recent findings in animal models show that lifespan is not exclusively encoded in genes, and that epigenetic factors such as DNA methylation and histone modification of the genome have important roles. Longevity is therefore regulated by both genetic and environmental factors. To decipher the relationship between longevity and factors such as diet, life style, faith and other variables, a large and unique human study, the Adventist Health Study (AHS2), was initiated at LLU in Loma Linda, CA, one of the five blue zones in the world where many people enjoy a long and healthy life span. We will use state-of-the-art next-generation sequencing (NGS) technologies and cutting-edge genomic and bioinformatic tools to map out the epigenomic and transcriptomic fingerprints that are characteristic of longevity. Using systems biology approaches our objectives are: 1) decipher genome-wide DNA methylation and its relationship with aging/longevity; and 2) determine long-term dietary (vegan) modulations and reprogramming of the epigenome and their relationship with aging. This study is in collaboration with Dr. Penelope Duerksen-Hughes and Dr. Gary Fraser.

6. Others: There are many other projects currently supported by the LLU Center for Genomics involving in genomics and bioinformatics in collaborating with many different investigators at LLU.