LiMCA – simultaneous single-cell three-dimensional genome and gene expression profiling

Understanding the relationship between a genome’s structure and its function is crucial. Yet, unraveling this relationship has long been a challenge for scientists, particularly when it comes to measuring both the three-dimensional (3D) genome structure and gene expression of individual cells simultaneously.

Enter ‘Linking mRNA to Chromatin Architecture (LiMCA)’—a groundbreaking technique that promises to shed new light on the complex interplay between the 3D genome and transcriptome. Developed by a team of researchers at Peking University, LiMCA offers unparalleled sensitivity and the ability to work with low-input materials, making it a powerful tool in the field of genomics.

Development of LiMCA

Fig. 1

a, Left, schematics of the LiMCA procedure. Right, the 20-kb resolution 3D genome structure of a representative cell; expressed genes are projected. RT, reverse transcription. b, Comparison of ensemble LiMCA and bulk Hi-C. The maximum intensity is indicated. c, Scatter-plot of the first eigen value between ensemble LiMCA and bulk Hi-C at 100-kb resolution. d, Scatter-plot of expression level (FPKM) between bulk RNA-seq and combined expression profile of LiMCA. e, The median contact number of LiMCA is compared to HiRES. f, Uniform Manifold Approximation and Projection (UMAP) embedding of four profiled cell lines based on gene expression profiles (left) or single-cell A/B values (right). The same cells are connected with lines. g, Contact matrices (left) around NFKB1, representing ensemble Hi-C data of NFKB1-high group (top left) and NFKB1-low (bottom right). Normalized contact frequency plot (right), centered at the NFKB1 upstream enhancer. h, Radial distribution of gene density; nucleus is sliced to 0.01 thickness. 

In a recent study, the scientists combined LiMCA with their high-resolution single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq), known as METATAC. This cutting-edge approach allowed them to delve into the chromatin accessibility, 3D genome structures, and gene expression profiles of individual developing olfactory sensory neurons—a feat previously thought to be unattainable.

By examining the dynamics of olfactory receptor (OR) enhancers, the researchers uncovered a wealth of new insights into the regulation of gene expression in these specialized neurons. They found that OR genes and their enhancers exhibit peak accessibility during early differentiation, suggesting a critical role in the developmental process.

Even more intriguing was the revelation of the dynamic spatial relationship between ORs and enhancers—a discovery that provides valuable insights into the intricate ‘one neuron–one receptor’ selection process. By deciphering the 3D connectivity of ORs and enhancers, scientists are beginning to unravel the mysteries behind how genes are selected and expressed in individual neurons.

The implications of this research extend far beyond the realm of olfactory sensory neurons. By unraveling the complex interplay between 3D genome architecture and gene expression, scientists are paving the way for a deeper understanding of cellular development and function across a wide range of biological processes.

Availabilityhttps://github.com/zhang-jiankun/LiMCA

Wu H, Zhang J, Jian F, Chen JP, Zheng Y, Tan L, Sunney Xie X. (2024) Simultaneous single-cell three-dimensional genome and gene expression profiling uncovers dynamic enhancer connectivity underlying olfactory receptor choice. Nat Methods [Epub ahead of print]. [article]

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