Genome folding has long been proposed to modulate gene expression. While many studies support this view, other findings challenge a simple or universal relationship between structure and function.
A major reason for this gap in understanding is that much of what we know comes from ensemble measurements. Because these measurements average over millions of cells and molecular conformations, they obscure the structural variability that exists from cell to cell and limit our ability to directly connect a given genome structure to its functional output. Our lab addresses this problem by studying genome organization and gene expression at single-cell resolution, allowing us to relate structure, transcriptional activity, and cell state in the same biological context.
Our research program is centered on understanding how genome architecture influences gene expression, and how both together shape cell fate decisions in development and disease. To do this, we combine multiplexed and correlative DNA and RNA imaging, super-resolution microscopy, and quantitative analysis approaches that enable us to directly link 3D genome structure with transcriptional output in individual cells.
More broadly, our lab is interested in how physical organization across scales shapes cell behavior. In addition to genome architecture, we study how cells sense and respond to the mechanical properties of their environment. This includes work on rigidity sensing and anchorage dependence in cancer, where we investigate how defects in mechanical sensing pathways allow tumor cells to evade anoikis and survive during dissemination. By connecting genome organization, transcriptional regulation, and cellular mechanics, we aim to understand how physical principles govern cell fate in both normal physiology and disease.
Current research directions:
Structural reorganization and transcriptional switches at compartmenal interfaces:
Is the breakage of active and inactive chromatin predictive of changes in gene expression? Here, we are investigating structural and functional changes that occur during several disease processes, such as aging and cancer. For instance, at the transition from proliferation to senescence, where we know of global changes in genome organization and gene expression, and a change in cell fate accompanies these. However, we do not know how these functional and structural changes are connected to each other, and whether they are intertwined? To answer that, we are focusing on chromosomal regions that switch their transcriptional state when the cell transforms from a proliferating to a senescent state.
Does the folding of regulatory elements within TADs dictate gene expression, and if so, how?
Loop domains are a genomic organizational unit, discovered by Hi-C studies, and confirmed by microscopy images. Loci within these domains interact with each other more frequently than with loci of other domains, whereas domain boundaries, enriched with CTCF motifs in mammals, have been shown to regulate gene expression by restricting the interaction of cell-type-specific enhancers with their target genes. However, recent studies have questioned the role of domains in regulating gene expression. For instance, our collaborators in the Mundlos laboratory have shown that domain fusion driven by CTCF boundary deletion, doesn’t necessarily affect gene expression. However, an inversion, which includes a boundary region, not only leads to domain fusion but also a considerable change in gene expression. Therefore, we still don’t really understand how structural variations may regulate gene expression. And, it’s very likely that averaging over millions of structures is precluding us from connecting a given structure to its resulting function. Utilizing correlative RNA/DNA imaging, we are hoping to determine the relationship between structural deformations and gene expression in developing mice.
Rigidity sensing, cell adhesion, and anoikis resistance in cancer
In parallel with our work on genome organization, we study how cancer cells respond to the mechanical properties of their environment. Normal cells rely on rigidity sensing and proper adhesion signaling to determine whether they are attached to a suitable extracellular matrix. Loss of these cues typically triggers anoikis, a protective cell death program that prevents inappropriate survival after detachment. Metastatic cancer cells, however, often bypass this safeguard. Our recent work examines how defects in rigidity sensing and compensatory survival pathways enable cancer cells to survive in suspension and resist anoikis. By identifying the molecular pathways that connect mechanical sensing, adhesion, and cell survival, this work expands our broader interest in how physical and structural regulation influences cell fate decisions in disease
Technology Development:
In addition to addressing fundamental biological questions, we continue to develop new experimental and computational tools for studying the genome at higher genomic, spatial, and temporal resolution. These efforts include advances in multiplexed imaging, correlative imaging strategies, and quantitative analysis pipelines that allow us to extract more information from single cells and directly test mechanistic models of genome organization.
Finally, and most importantly, we are open to new ideas. If you want to share your ideas and/or join our team, please email niguy@utmb.edu
Funding: We thank CPRIT and UT STAR for supporting us.