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Design in the 4th Dimension: The 4D Nucleome Project

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The Human Genome Project completed in 2003 was only the start of something far grander: understanding the entire “nucleome” of genetic activity. First there was the genome: the sequence of nucleotide bases. Then there was the transcriptome, the library of transcribed elements, studied by the ENCODE consortium. Then there was GENCODE and modENCODE, which elaborated the regulatory elements that modify transcription. Now, Nature has introduced the 4D Nucleome Project: an investigation of how all these factors interact in space and time.

The 4D Nucleome Network aims to develop and apply approaches to map the structure and dynamics of the human and mouse genomes in space and time with the goal of gaining deeper mechanistic insights into how the nucleus is organized and functions. The project will develop and benchmark experimental and computational approaches for measuring genome conformation and nuclear organization, and investigate how these contribute to gene regulation and other genome functions. Validated experimental technologies will be combined with biophysical approaches to generate quantitative models of spatial genome organization in different biological states, both in cell populations and in single cells. [Emphasis added.]

We have reason to expect more problems for Darwinism with this bold initiative. For one thing, there is no mention of evolution in the lengthy paper, or of natural selection or any other Darwinian term: fitness, beneficial mutation, selective pressure — nothing. There are, in contrast, plenty of design-friendly words, particularly function and regulation and their derivatives.

The human genome contains over 20,000 genes and a larger number of regulatory elements. Large-scale studies over the last decade have catalogued these components of our genome and the cell types in which they are active. The ENCODE, Roadmap Epigenome, International Human Epigenome Consortium, EpiGeneSys (http://www.epigenesys.eu/en/) and FANTOM projects have annotated thousands of genes and millions of candidate regulatory elements. However, our understanding of the mechanisms by which these elements exert regulatory effects on specific target genes across distances of kilobases, and in some cases megabases, remains incomplete.

Another reason for expecting good material for ID advocates is that the consortium is focused on looking for reasons for things. We can expect the junk DNA myth to continue to vanish.

In the section “Relating Structure to Function,” the authors describe how researchers in the 4D Nucleome Network will use tried-and-true methods of tweaking genes to see what breaks:

An important and overarching goal is to determine how genome structure and chromatin conformation modulate genome function in health and disease. To this end, the 4DN Network will explore experimental approaches to manipulate and perturb different features of the 4D nucleome. First, using CRISPR–Cas9 technologies, DNA elements involved in specific chromatin structures, for example, domain boundaries or chromatin loops, can be altered, re-located or deleted. Second, defined chromatin structures, such as chromatin loops will be engineered de novo by targeting proteins that can (be induced to) dimerize with their partner looping proteins (for example, ref. 7). Third, other CRISPR–Cas9 approaches will be used to target enzymes (for example, histone-modifying enzymes, structural proteins) or ncRNAs to specific sites in the genome. Fourth, several groups will perturb nuclear compartmentalization by developing methods for ‘rewiring’ chromosome regions to different nuclear compartments, either by integrating specific DNA sequences that are capable of autonomous targeting of the locus to different nuclear compartments or by tethering certain proteins to these loci to accomplish similar re-positioning. Fifth, cell lines will be generated for conditional or temporal ablation of nuclear bodies or candidate chromosome architectural proteins (such as CTCF and cohesin) or RNAs. Sixth, additional methods will be developed to nucleate nuclear bodies at specific chromosomal loci. Finally, biophysical approaches will be developed to micro-mechanically perturb cell nuclei and chromosomes followed by direct imaging of specific loci. Although it remains challenging to establish direct cause-and-effect relationships, analysis of the effects of any of these perturbations on processes, such as gene expression and DNA replication, can provide deeper mechanistic insights into the roles of chromosome structure and nuclear organization in regulating the genome.

“If it ain’t broke, don’t fix it,” the proverb goes, but sometimes breaking things is the best way to learn how something works. What happens if we change the shape of a chromosome? What happens if we remove a non-coding RNA (ncRNA), or send it to a different site? What happens if we “rewire” chromosome regions to different nuclear compartments? Experiments will allow teams to build up pictures of what elements regulate what processes.

Just as ENCODE teams at multiple institutions determined that most of the genome is transcribed, the 4D Nucleome Network is likely to find that most of the genome is functional.

After determining the complete DNA sequence of the human genome and subsequent mapping of most genes and potential regulatory elements, we are now in a position that can be considered the third phase of the human genome project. In this phase, which builds upon and extends other epigenome mapping efforts mentioned above, the spatial organization of the genome is elucidated and its functional implications revealed. This requires a wide array of technologies from the fields of imaging, genomics, genetic engineering, biophysics, computational biology and mathematical modelling. The 4DN Network, as presented here, provides a mechanism to address this uniquely interdisciplinary challenge. Furthermore, the policy of openness and transparency both within the Network and with the broader scientific community, and the public sharing of all methods, data and models will ensure rapid dissemination of new knowledge, further enhancing the potential impact of the work. This will also require fostering collaborations and establishing connections to other related efforts around the world, for example, the initiative to start a European 4DN project (https://www.4dnucleome.eu), that are currently under development. Together these integrated studies promise to allow moving from a one-dimensional representation of the genome as a long DNA sequence to a spatially and dynamically organized three-dimensional structure of the living and functional genome inside cells.

Exciting days are ahead. If the sequence alone was sufficient for a design inference, how much more will a 3-D spatial organization operating in the 4th dimension of time be likely to proclaim design?

The focus of this project on function is driving innovation. To accomplish their goals, researchers will have to come up with new instruments, techniques, and models. Instead of dismissing what they don’t understand as junk, they want to know what the nucleome is doing. This is healthy for science. It’s bound to engender profound discoveries, deepening our understanding of genetics and epigenetics. It’s bound to provide practical applications for health and medicine.

Let’s make some ID predictions: (1) The spatial arrangement of nuclear elements (such as chromosomes) will prove to be functional. (2) The time interactions of elements will prove to be functional. (3) Dan Graur will get angrier.

Image credit: Daniel79 via Pixabay.