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3D Genome
The genome is similar to yarn spooled and re-spooled to have efficient packing — if stretched out, a human genome would measure over 6 feet. Over the last century, the rules of genetics have been established along with characterization of the central dogma. Driven by new tools, the higher-order regulation (i.e. epigenetic) and spatial organization of the genome (3D genome; image below showing the levels of genomic complexity) is being characterized. As the research improves, parts of the 3D genome are becoming attractive therapeutic targets. The significance of the 3D genome will likely improve because the structure of the genome often determines its function.
Source: Nature
Interesting companies in the field are Foghorn, Cambridge Epigenetix, Gotham, Argonaut, and Constellation. There are also several liquid biopsy companies using epigenetic markers to improve their diagnostic capability. However, the field is still early with many discoveries to be made and form the basis of new companies. The top research labs making these discoveries are the Kleckner Lab and Dekker Lab who invented the initial toolkit to study the 3D genome, the Aiden Lab who is pushing the upper limits of these tools, and the Rinn Lab who studies the role of noncoding RNAs in establishing and maintaining the 3D genome.
Importantly, there are a set of rules for the 3D genome being characterized that drive the determinism of gene regulation. Genetic sequences loop (146 basepair DNA wrapped around a core histone octamer) and cluster to form topological-associating domains (TAD) where pairwise interactions within a TAD are more likely than outside one. These TADs cluster themselves — with active regions (euchromatin) in the center of the nucleus and inactive regions (heterochromatin) around the periphery. There are more subclasses within the two major regions determined by specific decorations of histone/DNA modifications and complexes. These higher genome structures are incredibly important for health as a little over 1% of the genome encodes proteins (i.e. the genome is not junk). Overall, each level of complexity is regulated by specific markers:
Source: Nature
History
In the 1980s, enhancers were discovered as regulatory elements within the genomes that control transcription. In the 1990s with human sequences coming online and the release of the human genome in the 2000s, genome-wide association studies(GWAS) found that most genetic variants linked to disease were non-coding. Around this time, tools emerged to begin to understand how these non-coding variants actually function. The two most important tools, 3C(2002) and Hi-C(2009) coupled with large-scale studies over the last decade helped drive our current understanding of the 3D genome. The ENCODE, International Human Epigenome Consortium, and other projects annotated the ~20K human genes, the genes’ regulatory modifications, and millions of regulatory elements within the genome. A recent study showed that each genome differs from the reference at about 4M-5M different sites. This work formed the basis for several epigenetic drugs inhibiting DNA methyltransferases and histone deacetylases. With the increasing power of tools to understand the 3D genome, the number of drugs brought to patients ought to only increase.
Toolkit
Two major methods have driven our understanding of the 3D genome:
- Imaging — fluorescence in situ hybridization (FISH) and live-cell imaging
- Chromosome capture (image below) to measure contact probabilities between genomic regions — chromosome conformation capture(3C), circular chromosome conformation capture(4C), chromosome conformation capture carbon copy(5C), chromatin interaction analysis paired-end tag(ChIA PET), and genome-wide chromosome conformation capture(HiC) — have carried most of the freight in the field as sequencing costs have decreased super-exponentially
Source: Nature
Combining this toolkit with other emerging inventions to gain detailed views of the 3D genome is a large opportunity:
- The use of single-cell sequencing to understand the diversity of 3D genomes within a tissue.
- The use of super-resolution microscopy to gain a much higher resolution inside living cells.
- The use of CRISPR to study specific genomic regions in the context of the 3D genome and functionally characterize chromatin interactions.
With these combinations, the translational potential of the 3D genome is becoming higher as new biomarkers are discovered and drugs developed against them.
Applications
More often than not, genetic variation associated with disease is located in non-coding regions, around 99% of the genome. This is a large opportunity to characterize the molecular basis of these associations and translate them into medicines (image below). For example, removing mutationsin a Myc enhancer have created mice resistant to intestinal tumors. Myc is a notorious undrugged target — due to its expression across a wide-set of tissues, inhibiting its activity a level or two of complexity up could enable higher levels of cell specificity with more control. Another great example, is the association of SATB1, a determinant of genome structure, in breast cancer. As systematic screens (i.e. RNAi, CRISPR) are done in patient samples, genome conformations that driven disease and the new targets that create the conformations will emerge. Examples of potential targets are CTCF, topoisomerase, and cohesin, which are important factors regulating chromatin interactions. Currently approved chromatin-modifying drugs show efficacy but also widespread changes in genome structure that may lead to deleterious effects. As the 3D genome is studied in particular diseases, the design of more precise drugs are likely to emerge.
The most exciting approach to solve this problem, is tissue/cell-specific chromatin editing. With the invention and development of CRISPR, the ability to target specific interactions, either histone modifications, TAD organization, or something else, within a genome in a reversible way is powerful.
Source: Nature
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