Multi-omic profiling: Combining epigenomics and gene expression in a single cell

By Aditya Pai, Vice President, Corporate and Business Development, MedGenome Inc.

In my previous blog, I highlighted the uniqueness of single cell RNA sequencing technologies and how these can be used to understand 5’ and 3’ gene expression, T and B cell immune repertoire profiles, and more specific antibody-based approaches such as CITE-Seq as well as epigenetics approaches with ATAC-Seq. In this blog, the power of multi-omic approaches to simultaneously determine open chromatin regions with gene expression in a single cell is reviewed.

Understanding the epigenetic profile of cells in development and / or disease can provide unique and key insights into understanding the expression of genes during such processes. Epigenetic changes don’t change the DNA sequence but instead involve the attachment of chemicals. Methylation, acetylation and two examples of such processes and such processes are linked to gene regulation and many physiological and pathological processes. In DNA methylation for example, methyl groups attach to DNA rendering it inactive and thus preventing the creation of a specific protein. RNA can be methylated and acetylated as well. Such epigenetic modifications can impact RNA processing, mRNA translation into proteins. Two very distinct syndromes, Prader-Willi syndrome and Angelman syndrome demonstrate how a single locus on chromosome 15q11.2-q13.3 can be deleted or mutated and depending on maternal or paternal imprinting can result in very different phenotypes. DNA methylation is at the heart of both syndromes and epigenetics has allowed for a greater understanding of both syndromes.

Epigenetic changes are studied by several techniques such as the understanding the modification of histone proteins around which DNA is bound. Chromatin immunoprecipitation-sequencing (ChIP-seq) has historically been used as a method for understanding protein-chromatin interactions. ChIP-seq has limitations such as requiring a large number of cells, lengthy protocols, and high sequencing depth. For “bulk cell” studies, more recent methods include CUT and TAG and CUT and RUN (cleavage under targets and Tagmentation or release using nuclease respectively). In such methods, DNA fragments bound to the modified histones are directly cleaved and released, instead of more laborious ChiP-seq methods requiring cross-linking and subsequent immunoprecipitation.

Single cell-based methods like ATAC-Seq, 5’ and 3’ gene expression or multi-omic approaches such as ATAC-Seq with 3’ gene expression offer unique insights to our clients compared to bulk RNA approaches.

Single cell ATAC-seq or assay for transposase-accessible chromatin looks for regions of open chromatin which provide insights into those regulatory sequences which are accessible to DNA binding proteins. ATAC-seq can be combined with 3’ gene expression simultaneously in a single cell providing multi-omic information and insights into how chromatin structure influences regulation of gene expression

Takeaway summary:

ATAC-Seq and 3’ gene expression are useful to simultaneously perform in a single cell and can help in the following ways:

  1. Deeper cell type characterization where epigenetic profiles can be overlayed with gene expression to allow for better interpretation of such profiles
  2. Understanding how gene regulatory networks may be disrupted in disease
  3. Finding new gene regulatory interactions using multi-omic data.

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