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Developmental biology - Evolutionary Genetics

How Elements in DNA Regulate Cell Type

Scientists complete a major map of the mouse genome revealing gene regulation at the single-cell level...

Scientists have completed a map of the regulatory landscape of a mouse genome revealing how regulation occurs at the single-cell level. The team applied a special assay previously developed to profile the genomic feature called chromatin accessibility. The atlas provides an understanding of specific DNA elements as each regulates the identity of varying cell types.

Researchers are interested in how DNA winding, wrapping and packaging into what we call chromatin influences how and what genetic information is made available within each individual cell. DNA is like a string of beads. Spaces form when particular molecular 'beads' are moved so that proteins can access and 'read' their gene information. A state identified as 'chromatin accessibility.'

In this study, almost a hundred thousand individual cells from 13 adult male mouse tissues were assayed. The tissues included: bone marrow, large intestine, heart, kidney, liver, lung, small intestine, spleen, testes, thymus, the whole brain and the cerebellum and prefrontal cortex of the brain.
Scientists observed 85 distinct chromatin accessibility patterns, assigning most of these to specific cell types. They also cataloged more than four hundred thousand potential regulatory elements. In general, they were able to identify clusters of cells with similar chromatin landscapes, and then examined each cluster to pick out diverse cell types.

They observed how the quality of their data varied, largely dependent on tissue type. Data of the lowest quality was in sperm progenitor cells found in the testes, as DNA is packaged differently in reproductive cells.

The data gleaned in this atlas could advance understanding of developmental pathways and the formation of cell lines. For example researchers can use the map to understand how chromatin accessibility changes as immature blood-forming cells turn into mature blood cells with specific roles.

This single-cell atlas is part of an ongoing effort among labs around the world to compile a comprehensive atlas of cell types for humans, mice and other species. Shendure, Trapnell and collaborating labs have already generated related atlases for developing worms and flies. Their methods and findings are published Aug. 2 in the journal Cell (1).

Senior authors on the study were Cole Trapnell and Jay Shendure, both faculty in the Department of Genome Sciences at the University of Washington School of Medicine, and members of the Paul G. Allen Discovery Center for Cell Lineage Tracing and the Brotman Baty Institute for Precision Medicine in Seattle. Shendure is also a Howard Hughes Medical Institute investigator. Darren A. Cusanovich, a former postdoctoral fellow, and Andrew J. Hill, a graduate student, both working in Shendure's lab, headed the study. Cusanovich and his colleagues developed the single-cell combinatorial indexing assay protocols critical to this research.

Trapnell explained how most previous studies averaged across many different cell types, which can obscure what's going on in individual cell types. "We're interested in genomic properties of cells at the single cell level," adding that most research in this area focused on whether expression of certain genes in cells are either on or off and less on why or how genes become activated or silenced. Researchers used the resulting data to identify parts of the genome 'open' in different cell types and the genes these elements regulate. They then intersected the atlas with the results of human genome-wide association studies, to uncover gene variants and possible disease links.
Researchers were thus able to implicate cell types playing a role in many common human disorders and physical traits, despite that cell atlas data came from mice and not humans. For example, heritability for Alzheimer's disease was not enriched in any class of brain cells known as neurons, but strongly enriched in microglia, which defend the nervous system. By contrast, the strongest enrichments of heritability for bipolar disorder were in excitatory neurons.

Other traits examined included autoimmune conditions, high lipid levels, immunoglobulin deficiencies, body size and composition, asthma, hay fever, heart attacks, gout and a host of other conditions or characteristics. Related work led by UW Medicine researchers, published Aug. 2 in Molecular Cell (2), introduced Cicero, an algorithm named for the Roman orator, that assists in determining the grammar of gene regulation. This method taps into single-cell chromatin accessibility data, linking regulatory elements in DNA to the genes they target.

The software, written by Hannah Pilner, a graduate student in both the Trapnell and Shendure labs, also determined how thousands of regulatory elements orchestrate gene expression in developing muscle cells. The scientists were able to use Cicero in the mouse atlas to build a map of potential connections between regulatory elements in each cell type. They hope this sort of mapping will reveal how the millions of regulatory DNA sequences in the genome control how cells perform specialized functions.
The average adult human contains approximately 37 trillion cells that vary in type, abundance and state of development. So the production of a human cell atlas is a daunting task owing to such a vast number and the many different types of cells thought to exist over one individual's life span.

Progress described in both of these papers might aid in the creation of a human cell atlas. The researchers point out that what was once labor intensive to accomplish for a handful of cell types can now be done at single-cell resolution in just a few months. In contrast to a human, a house mouse is thought to have only about 10 billion cells in its body (approximately 0.02% as many as in the human body). Humans and mice diverged from a common ancestor about 75 million years ago. Yet despite the genetic changes that have occurred since their division, the mouse provides many clues to human health and disease. Because of their joint evolutionary relationship, the mouse cell atlas will contribute to understanding how other mammalian, including human, cell types arose.

(1) A Single-Cell Atlas of In Vivo Mammalian Chromatin

The regulatory landscape of adult mouse tissues mapped by single-cell chromatin assay Characterization of 85 distinct chromatin patterns across 13 different tissues Annotation of key regulators and regulatory sequences in diverse mammalian cell types Dataset allows resolution of cell types underlying common human traits and diseases.

We applied a combinatorial indexing assay, sci-ATAC-seq, to profile genome-wide chromatin accessibility in ~100,000 single cells from 13 adult mouse tissues. We identify 85 distinct patterns of chromatin accessibility, most of which can be assigned to cell types, and ~400,000 differentially accessible elements. We use these data to link regulatory elements to their target genes, to define the transcription factor grammar specifying each cell type, and to discover in vivo correlates of heterogeneity in accessibility within cell types. We develop a technique for mapping single cell gene expression data to single-cell chromatin accessibility data, facilitating the comparison of atlases. By intersecting mouse chromatin accessibility with human genome-wide association summary statistics, we identify cell-type-specific enrichments of the heritability signal for hundreds of complex traits. These data define the in vivo landscape of the regulatory genome for common mammalian cell types at single-cell resolution.

Authors: Darren A. Cusanovich, Andrew J. Hill, Delasa Aghamirzaie, Christine M. Disteche, Cole Trapnell and Jay Shendure.

(2) Cicero Predicts cis-Regulatory DNA Interactions from Single-Cell Chromatin Accessibility Data

• Cicero connects regulatory DNA elements to target genes
• Co-accessible elements form chromatin hubs
• Chromatin hubs are co-regulated during skeletal muscle development
• Cicero can help reveal the mechanisms of cis-regulation on a genome-wide scale

Linking regulatory DNA elements to their target genes, which may be located hundreds of kilobases away, remains challenging. Here, we introduce Cicero, an algorithm that identifies co-accessible pairs of DNA elements using single-cell chromatin accessibility data and so connects regulatory elements to their putative target genes. We apply Cicero to investigate how dynamically accessible elements orchestrate gene regulation in differentiating myoblasts. Groups of Cicero-linked regulatory elements meet criteria of “chromatin hubs”—they are enriched for physical proximity, interact with a common set of transcription factors, and undergo coordinated changes in histone marks that are predictive of changes in gene expression. Pseudotemporal analysis revealed that most DNA elements remain in chromatin hubs throughout differentiation. A subset of elements bound by MYOD1 in myoblasts exhibit early opening in a PBX1- and MEIS1-dependent manner. Our strategy can be applied to dissect the architecture, sequence determinants, and mechanisms of cis-regulation on a genome-wide scale.

Authors: Hannah A. Pliner, Jonathan S. Packer, José L. McFaline-Figueroa, Darren A. Cusanovich, Riza M. Daza, Frank J. Steemers, Jay Shendure and Cole Trapnell.

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Aug 10, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

Artist's conception of a mouse cell atlas suggests clustering of single-cell chromatin accessibility, colored by tissue, as a start to identifying diverse cell types. Image Credit: Andrew Hill.

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