Research

Current focus

Thanks to advances in the next generation sequencing technologies, many thousands of noncoding RNAs (ncRNA) and regulatory elements called enhancers have been identified throughout the human genome. Recent studies, including our own, pointed to the novel role of ncRNAs in coordinating with proteins to drive gene expression in a cell-type specific manner via chromatin modulation (Trinh et al, Blood J, 2021). Nevertheless, most ncRNAs and enhancers remains to be precisely mapped and functionally defined. The research goals of the Trinh lab are to understand how proteins and ncRNAs coordinate in controlling gene expression, and to identify novel RNA regulators of cancer-associated genes for therapeutic development (Fig. 1). Specifically, we focus on understanding the role of proteins and RNAs via modulation of chromatin architecture in normal and malignant myelopoiesis, and myeloid cell-tumor cell communication in the tumor microenvironment as well as cancer drug resistance. To that end, the lab employs a combination of experimental and computational approaches.

Dr. Trinh talked about our the research program on UVA School of Medicine Medicine in Motion News

1. Protein-ncRNA coordination in myeloid cell development and AML

Failure in myeloid cell maturation is the cause of acute myeloid leukemia (AML), a blood cancer with very poor patient outcome. We hypothesize that ncRNAs coordinate with proteins, in governing expression of important myeloid genes via chromatin looping, and that aberrations in this molecular coordination contribute to AML progression (Fig. 2). To this end, we are 1) comprehensively characterizing protein-binding ncRNAs and demonstrate the effect of Protein-ncRNA coordination on chromatin architecture and epigenetic marks at myeloid gene loci, 2) determining ncRNA regulators of myeloid gene expression, and 3) demonstrating that fusion proteins exhibits their oncogenic functions through modulating ncRNAs. These studies will provide important mechanistic insights into protein- and ncRNA-mediated gene regulation in normal development and cancer progression.

Figure 2. Working model for gene regulations by ncRNAs and proteins via chromatin structure in normal myeloid development and AML. E: Enhancer, P: Promoter

2. Protein-ncRNA coordination in cancer drug response

Drug resistance is a major problem in cancer treatment. To comprehensively investigate the role of ncRNA-protein mediated gene regulation via chromatin structure in drug response, we are 1) leveraging bioinformatic and biostatistical analyses of big data sets in identifying protein-ncRNA candidates that are responsive to popular cancer drugs, 2) developing genome wide CRISPR screens to identify ncRNA modulators of drug responses, and 3) determining ncRNA-mediated regulatory mechanisms in drug sensitivity. The goals are to identify and establish ncRNAs and proteins as diagnostic biomarkers and therapeutic targets (Fig. 3).

Figure 3. Flowchart of studies for protein-ncRNA coordination in drug response

3. Protein-ncRNA coordination in the tumor microenvironment

This line of study combines our current expertise in myeloid cell research and earlier experience with solid cancer research. Increasing evidence indicate the important role of myeloid cells in solid cancer progression but the molecular mechanisms by which these immune cells and tumor cells communicate with each others within the tumor microenvironment is not well understood. Using experimental and bioinformatics methods, we are investigating the role of protein-ncRNA hubs in myeloid cell-cancer cell communication and their effects on tumor hallmarks (Fig. 4).

Figure 4. Protein-ncRNA crosstalk in myeloid cell-cancer cell communication in the tumor microenvironment

4. Therapeutic strategies "renormalizing" chromatin structure

We are developing therapeutic approaches based on protein-ncRNA hubs that control the formation of gene-activating chromatin loops. The goal is to renormalize chromatin structures in cancer cells toward what seen in normal cells leading to normal cell growth and differentiation (Fig. 5).

Figure 5. Toward renormalizing chromatin structures

Earlier research

In previous research, we investigated regulatory mechanisms mediated by tumor-promoting proteins that function as transcription factors in cancer and normal cells. This leads to several mechanistic findings, explaining cancer resistance to the antigrowth factor TGF-b (Trinh et al, Oncogene, 2009) and chemotherapeutic drugs (Trinh et al, Cancer Res, 2013), tumor angiogenesis and metastasis (Haria, Trinh et al, Am J Pathol, 2015; Trinh et al, Mol Cancer 2015) as well as normal blood cell development (Trinh et al, J Cell Sci, 2015). Learn more