Under Construction
Spatial Transcriptomics
The Han Lab investigates the mechanistic underpinnings of MERFISH, probing how combinatorial binary barcode design, probe hybridization kinetics, and photobleaching dynamics jointly determine detection fidelity and multiplex capacity. We systematically leverage nucleic acids probes, fluorescence-label chemistry, and hybridization stringency to uncover the chemical principles that govern probe–target binding specificity and signal-to-noise performance. By coupling iterative rounds of hybridization and imaging with rigorous error-robust decoding algorithms, we elucidate how code diversity and Hamming-distance thresholds minimize classification errors even in densely labeled samples. These mechanistic insights into sequential hybridization cycles and error-correction schemes form the basis for engineering next-generation spatial transcriptomics platforms with enhanced throughput, accuracy, and gene multiplexity.
High-Throughput Spatial Transcriptomics Imaging Platform
The biology of multicellular organisms is structured at multiple levels. Networks of molecules govern each cell’s functions, and cells interact with their surrounding environment to refine their states, giving rise to behavior. In this world, RNA is the dynamic readout of gene activity to tell us which programs a cell is running. Yet knowing which transcripts are present isn’t enough given that their spatial locations indicate how cells influence one another and how tissues function as a whole. Therefore, imaging-based spatial transcriptomics addresses this amazingly by barcoding individual RNA molecules and mapping their exact locations within intact tissue to produce quantitative gene-expression atlases with native tissue architecture. In the Han Lab, we’ve built a fully modular, high-throughput platform that captures single-molecule resolution in detecting RNA while preserving their spatial coordinates.
Analytical Method Development
Our lab develops innovative analytical methods to advance the study of spatial transcriptomics, enabling a deeper and more comprehensive understanding of gene expression within intact tissues. Traditional single-cell RNA sequencing, while powerful, often fails to capture key transcriptomic signals—such as those located in neurites, extracellular spaces, or fragile and rare cell types—due to the need for tissue dissociation. To address these limitations, we focus on designing computational frameworks that can identify and recover these overlooked components directly from spatial transcriptomics data. Our approaches allow for the detection of subtle transcriptional patterns, the separation of somatic and non-somatic gene expression, and the characterization of cell types or biological structures that are underrepresented in conventional analyses. We also develop tools to investigate the spatial relationships between individual RNA molecules within cells, uncovering patterns of subcellular organization and potential regulatory interactions. Complementing these computational efforts, we integrate high-resolution imaging technologies that provide nanoscale localization of transcripts, offering unprecedented insight into the spatial dynamics of gene regulation. Together, these analytical advancements enable a more accurate and nuanced interpretation of spatial omics data, with broad applications in neuroscience, cancer biology, and developmental systems.
Publications
Kim, Y. J.; Ojha, A.; Schrader, A..; Lee, J.; Wu, Z.; Traniello, I. M.; Robinson, G. E.*; Han, H.-S.*; Zhao, S. D.*; Sinha, S.* “SpaceExpress: a method for comparative spatial transcriptomics based on intrinsic coordinate systems of tissues”, submitted.
Kumar, A.; Schrader, A. W.; Boroojeny, A. E.; Asadian, A.; Lee, J.; Song, Y. J.; Zhao, S. D.*; Han, H.-S.*; Sinha, S.* “Intracellular Spatial Transcriptomic Analysis Toolkit (InSTAnT)”, Nature Communication, 2024, 15, 7794.
Yeo, S.; Schrader, A. W.; Lee, J.; Asadian, A.; Han, H.-S.* “Spot-Based Global Registration for Sub-pixel Stitching of Single-Molecule Resolution Images for Tissue-Scale Spatial Transcriptomics”, Analytical Chemistry, 2024, 96(17), 6517-6522.
Spatial Omics Platform Development
We built advanced spatial omics platforms to enable high-resolution, multiplexed analysis of gene expression within intact tissues. In our lab, we have built and implemented MERFISH, a powerful imaging-based spatial transcriptomics technology that allows for the precise localization of thousands of RNA species at subcellular resolution. This platform supports our broader efforts to dissect tissue architecture, uncover spatial gene regulation, and understand cellular interactions in complex biological systems.
Publications
Anacleto, A.; Cheng, W.; Feng, Q.; Cho, C.-S.; Hwang, Y.; Kim, Y.; Si, Y.; Park, A.; Hsu, J.-E.; Schrank, M.; Teles, R.; Modlin, R.L.; Plazyo, O.; Gudjonsson, J.E.; Kim, M.; Kim, C.H.; Han, H.-S.*; Kang, H.M.*; Lee, J.H. * “Seq-Scope-eXpanded: Spatial Omics Beyond Optical Resolution”, submitted. article
