Spatial Epigenome-Transcriptome Co-profiling via Microfluidic Tn5 Delivery
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Solution Overview
Problem
Current technologies lack the capability to perform unbiased genome-wide co-mapping of the epigenome and transcriptome on the same tissue section at a cellular level, failing to provide comprehensive understanding of gene regulation mechanisms.
Innovation Solution
A method involving the delivery of reagents with Tn5 transposition complexes and barcoded polynucleotides through microfluidic devices for spatially resolved epigenomic and transcriptomic profiling, allowing for the construction of spatial maps by correlating barcoded conjugates with sequencing reads.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If current spatial omics technologies are used, then spatial information can be captured, but only one layer of omics information can be profiled at a time
Solution Approach 1:
The patent combines spatial epigenomics and spatial transcriptomics into a single integrated assay, allowing simultaneous profiling of both omics layers on the same tissue section. This merging approach enables capture of multiple omics information layers (chromatin accessibility via ATAC-seq and gene expression via RNA-seq) while maintaining spatial context, resolving the contradiction between quantity of omics layers and device complexity
Solution Approach 2:
The methodology creates a universal platform that can profile multiple types of biological information (epigenetic and transcriptomic) using a single technical approach. The system is designed to handle diverse omics layers through common processing steps including tissue permeabilization, in situ tagmentation, reverse transcription, and library preparation, making the device/system multi-functional across different omics modalities
2Loss of information
If computational methods are used to integrate data from multiple omics, then data integration can be achieved, but the mechanistic link between different omics layers cannot be readily uncovered
Solution Approach 1:
The patent performs preliminary spatial mapping by capturing both epigenetic and transcriptomic signals in their native spatial context before any computational integration. By establishing the spatial coordinates and relationships in situ, the method preserves the mechanistic links between regulatory elements and target genes, allowing downstream analysis to reveal causal relationships rather than just correlations
3Adaptability or versatility
If imaging-based DNA seqFISH+ combined with RNA seqFISH is used, then spatial chromatin and gene expression can be detected, but only for target genes and genomic loci, not genome-wide
Solution Approach 1:
The patent replaces the imaging-based FISH approach with a sequencing-based methodology. Instead of using fluorescent probes and microscopy to detect specific targets, the method employs in situ tagmentation followed by NGS library preparation and sequencing. This substitution enables genome-wide unbiased profiling because sequencing can detect any genomic region or transcript without requiring prior knowledge of specific targets, thus achieving genome-wide coverage while simplifying the overall approach
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Enables simultaneous profiling of chromatin accessibility and gene expression at high resolution, linking epigenome to transcriptome pixel-by-pixel, and providing insights into gene regulation within tissue architecture.
Implementation Method 1
delivering to a region of interest in a tissue sample mounted on a substrate reagents for transposition including a Tn5 transposition complex pre-loaded with a DNA adapter containing a universal ligation linker
Implementation Method 2
delivering to the region of interest ligation reagents to join the ligation adaptor to the barcoded polynucleotides of the first set
Implementation Method 3
delivering to the region of interest a first set of barcoded polynucleotides, wherein the first set of barcoded polynucleotides is delivered through a first microfluidic device clamped to the region of interest
Data Source
AI summary
Provided herein are compositions and methods for high resolution spatial transcriptomic and epigenomic co-profiling of a biological sample.