1 DNA double helixThe carefully folded DNA information code stuffed into each of our trillions of cells maintains its specially formed 3D shape without forming snarled knots.  The regulatory switches that control the activation of our genes can be linearly far away, but the 3D wiring structure in fact keeps them physically in close proximity to those genes. 

How Can it All Fit?

Anyone who has opened a Christmas package and later tried to put the present back into that same package can relate to the problem of squeezing our DNA into the tiny nucleus of a cell.  If it were unwound into one long thin thread, the DNA code would be over six feet long and have to fit back into a small volume at the nanometer (billionths of a meter) scale of size.  If our DNA were the size in diameter of a tiny human hair-width thread and 13.4 miles long, the length of the island of Manhatten in New York City, it would have to be stuffed back into a volume the size of a marble.[i] 

Many of the illustrations in this article come from the science news articles and technical papers from the Encyclopedia of DNA Elements (ENCODE) project.

“No Knot” DNA Folding

How can the DNA squeeze into such a compact space and not be hopelessly tangled and knotted like a rope thrown up on a shelf, fishing line stuffed into a tackle box or a garden hose that keeps tangling in spite of efforts to loop it carefully?

 

2 tangled fishing linesOur experience with tangled fishing line shown in this photo makes us wonder how DNA can be so compact and yet not become tangled.[ii]

This next illustration shows a representation of part of a DNA chromosome color coded for different gene segments. The DNA structure is folded in complicated ways to connect the regulatory switch controls to the genes that they control.  The “ramen noodle”-like threads amazingly do not get tangled into knots in the squeezing process, but easily fold and unfold to read and copy the essential DNA sequences that control all aspects of a cell’s life. 

3 color coded DNA“In the fractal globule (above left), nearby regions on a chain of DNA-[the linear sections] indicated using similar colors-are packed into nearby regions in 3D space. The accessible DNA chain unravels easily (above right) because the globule lacks knots.” The compressed structure uses “a rare geometric shape observed in snowflakes, crystals and broccoli.”[iii]

The DNA Must Maintain a Specific 3D Shape to Function

The next illustration shows a closer zoomed in view of the DNA chains, showing the intricate 3D structure necessary to connect the gene bearing regions (in different colors again) and the associated control regulators shown in colored dots. Even as the DNA is stuffed into the nucleus, it still must maintain this 3D structure in order to function-think iPod form fitting plastic case that keeps its shape and has just the right amount of flexibility to pop the iPod in and out. The DNA is wired together by the carefully folded 3D shape.

4 DNA GENEA new approach to visualizing the physical and structural attributes of chromosomes to provide scientists with realistic 3D models that will help them better understand which parts of a genome are interacting with one another (integrated modeling platform or IMP).”[iv]
















In making advanced computer chips, a multiple level architecture is used so that the right components are electrically connected.  Here is a diagram of a multilayer chip.

5 multilayerAlso working at the nanometer level of detail, modern computer chips are designed using multiple layers to pack more transistors and other devices on a single chip. This use of multiple layers to connect components electrically through the layers is somewhat similar to the DNA having to have the regulator portions wound around and compressed into 3D space to be close to the genes they regulate.[v]

Incredible 3D Microscopic Tools

Now let’s zoom into this last and most detailed illustration to see the folding structures and how regulatory connection points can even span between chromosomes.  The subportions of the figure go from a linear map showing two chromosomes and three regulatory connection points to the thousand-base closeup that the cell exploratory tool (called Hi-C) developed by Job Dekker and his team at the University of Massachusetts have used to make many of the ENCODE project’s revolutionary discoveries.

6 zoom 

A two chromosome linear mapping in (A) then shows the interchromosome connections in (B).  The million base intermediate scale zoom level in (C) continues to the thousand base fine scale zoom level in (D) showing how the regulatory connection points (1, 2 and 3) fit into 3D space to be in close contact with the genes they control.[vi]

Additional Witness from Science of the Hand of God

The most important witness of the existence of God and His hand in our lives and in the universe is a spiritual witness through the Holy Ghost.  The evidences of scientific research can then be an additional faith-strengthening witness of His mighty hand in all things.  As stated by Alma:  “All things denote that there is a God”(Alma 30:44)

Particularly as we see these overwhelmingly complex miracles in the tiny living cell, we should, with Moroni, ask this important question:  “Who shall say that it was not a miracle that by his word the heaven and the earth should be; and by the power of his word man was created of the dust of the earth?” (Mormon 9:17)

What an amazing age we live in where the Lord has given us the ability to zoom into a cell using our microscopic tools and to begin to understand the actual control codes of the cells that give us life.


  As Moses declared on the shore of the Red Sea: “Fear ye not, stand still, and see the salvation of the Lord, which he will shew to you today.” (Exodus 14:13)

______________________________________


[i] Janelle Weaver, “New Technology Reveals Genome’s 3D Shape,” News Bytes, Simbios, the NIH National Center for Physics-Based Simulation of Biological Structures, Biomedical Computation Review, Winter 2009/2010. [http://biomedicalcomputationreview.org/6/1/5.pdf ]

Try taking a human hair as long as Manhattan and cramming it-unsnarled-inside a marble. This is the challenge faced by a 2-meter-long strand of DNA as it folds into its compact array of 23 chromosomes within a cell’s nucleus. Previously, scientists only theorized about how DNA squeezes inside a nucleus without becoming a hopelessly tangled mass. Now a new technique called Hi-C reveals that DNA packs knot-free into its chromosomal patterns by assuming a rare geometric shape observed in snowflakes, crystals and broccoli.”

 “Simulations revealed that DNA assembles into dense fractal globules-structures that look alike at different levels of magnification, such as the intricate geometrical form of a crystal. Genes are easily accessible, but when they’re not in use, the structure spontaneously collapses into a tight, knot-free bundle.” [Emphasis added]

[ii] Chris Brogan, “Untangled,” september 14, 2011, http://www.chrisbrogan.com/untangled/.

“We go about our lives quite tangled up with other people’s lives, whether we want to admit that or not. We carry with us tangles from our past connections, and tangles from worries about future events that haven’t even unfolded yet. These tangles affect our choices and decisions and feelings all the time, if we let them.”

[iii] Janelle Weaver, op. cit., http://biomedicalcomputationreview.org/6/1/5.pdf.

[iv] Jim Fessenden, “Realistic 3D models help scientists understand genome interaction,” University of Massachusetts Medical School, UMASS med NOW, 2012, http://www.umassmed.edu/news/articles/2010/3D_imaging.aspx.

 “Scientists know that the shape and structure of the human genome varies from cell to cell depending on which genes are active. Current efforts to study the human genome, however, are often done in a two-dimensional, linear sequence, an approach that fails to adequately account for how the physical shape and structure of the genome contributes to its ability to regulate genes and carry out tasks. Recent insights indicate that genetic elements spaced far apart along the genome may, in fact, be interacting thanks to “folding” or “looping” that brings them into close physical proximity-much like folding a narrow piece of paper down the middle brings the ends into contact.

“‘Having a 3D image of a chromosome tells us where to look for areas of the genome that we may not know are interacting,’ said Job Dekker, PhD, associate professor of biochemistry & molecular pharmacology and molecular medicine and lead researcher on the study. ‘It could help identify new genes that are active in diseased cells or regulatory elements that are helping to control those genes.’

“The team’s research details how genetic interaction and spatial proximity data can be translated into an accurate 3D model of a chromosomal segment using a computational model known as integrated modeling platform (IMP). To test their method, Dr. Dekker and colleagues focused on nearly identical, 500 kilobase segments on human chromosome 16 in two different types of cells-a lymphoid cell and a leukemia cell. An already extensively studied region of the genome that houses a number of active genes responsible for basic cellular maintenance regardless of cell type, chromosome 16 differs in one important way in these two cells: a group of genes not active in the lymphoid cells are highly expressed in the leukemia cells, giving Dekker and colleagues a readily identifiable model for comparison.”

[v] Steve Dai, “Multilayer Ceramic Microsystems: Applications in wireless, energy and life sciences” slide show, slide #15, Microtechnology Research Lab, Solid State Research Center, Motorola Labs (Tucson, Arizona), August 4, 2009, http://www.slideshare.net/SteveDai/ceramic-microsystems

A great presentation showing the amazing world of microchip design using 3D space via multiple layers of silicon. See also this more detailed diagram showing how an RF device using this technique is designed using the different levels to connect the various essential electrical pathways together (RF Device Elemental Structures: Slide #14 in presentation).


1F RF device

[vi]   Natalia Naumova and Job Dekker, “Integrating one-dimensional and three-dimensional maps of genomes,” Journal of Cell Science, Figure 2, 2013. http://jcs.biologists.org/content/123/12/1979.full.  

 Summary: “Genomes exist in vivo as complex physical structures, and their functional output (i.e. the gene expression profile of a cell) is related to their spatial organization inside the nucleus as well as to local chromatin status. Chromatin modifications and chromosome conformation are distinct in different tissues and cell types, which corresponds closely with the diversity in gene-expression patterns found in different tissues of the body. The biological processes and mechanisms driving these general correlations are currently the topic of intense study. An emerging theme is that genome compartmentalization – both along the linear length of chromosomes, and in three dimensions by the spatial colocalization of chromatin domains and genomic loci from across the genome – is a crucial parameter in regulating genome expression. In this Commentary, we propose that a full understanding of genome regulation requires integrating three different types of data: first, one-dimensional data regarding the state of local chromatin – such as patterns of protein binding along chromosomes; second, three-dimensional data that describe the population-averaged folding of chromatin inside cells and; third, single-cell observations of three-dimensional spatial colocalization of genetic loci and trans factors that reveal information about their dynamics and frequency of colocalization.” [emphasis added]

Figure 2 Caption:

“3D genome analysis. The spatial organization of genomes can be studied using single-cell methods or using population-based methods, and at different resolutions or length scales (A-D). (A) A hypothetical pair of metaphase chromosomes. 1D compartmentalization is indicated: constitutive heterochromatin domains include the centromere (cen), pericentromeric heterochromatin (subcen het) and telomeres (tel). Chromosome arms further consist of alternating active and repressed domains (indicated by different colors). Numbers indicate (chromosomal) regions to be analysed by 3D methods in panels B, C and D. (B) Spatial organization of chromosomes shown in A in the interphase nucleus. Chromosomal regions that are located far apart on the same chromosome (2 and 3) or located on different chromosomes (1 and 2, 1 and 3) can colocalize in 3D to form spatial compartments. (C) A higher-resolution (Mb scale) analysis of cis and trans associations of chromosomal regions 1 to 3 shown in B. At this resolution, associations of groups of genes can be detected surrounding subnuclear structures such as transcription factories (green circles) and splicing bodies [characterized by the presence of the splicing factor SC35 (red)].


For example, a trans interaction between regions 1 and 2 can occur through colocalization to the same transcription factory … or to two different transcription factories that are both associated with one SC35 granule …. (D) High-resolution (Kb scale) analysis of 3D folding and long-range associations that can be studied using 3C-based methods. At this scale, specific looping interactions can be detected between genes and regulatory elements. This scheme provides an example of a 3C analysis in which the interaction probability of a single defined genomic element is mapped throughout the larger region 3 (right). Peaks in this 3C map indicate long-range interactions that suggest a looped conformation (indicated on the left).”