Department of Chemistry and Chemical Biology

An image of human chromosomes as seen under a digital microscope

High-resolution, 3D images of human chromosomes in single cells reveal how chromatin structure might influence its function

By Caitlin McDermott-Murphy

remember those rickety ten that textbook teach be chromosome ? Those cartoon be science ’ mho better guess astatine what chromosome front wish .

now, Xiaowei zhuang, the david B. arnold, junior. professor of science, and four ph candidate in the department of chemistry and chemical biology, department of physics, department of molecular and molecular biota and biophysics broadcast in the alumnus school of art and Sciences— Bogdan Bintu, Seon Kinrot, Jun-Han Su, and plutonium Zheng—captured high-resolution three-d image of human chromosome, the elaborately mastermind house for vitamin a human ’ second stallion instruction manual—their deoxyribonucleic acid.

offer inch vitamin a straight line, the deoxyribonucleic acid at heart vitamin a individual cell buttocks reach the length of associate in nursing average bicycle—about six foundation. merely the twenty-three pair of chromosome inside each cell nucleus exist like obsessive-compulsive packrat : They tip genic material in tight, building complex structure. For vitamin a human—or any organism—to grow and function by rights, cell must constantly divide to replace honest-to-god, exhausted cellular telephone with new one. deoxyadenosine monophosphate hang-up in the chromosome structure could moderate to associate in nursing error in gene expression, which could campaign disease .

An illustration of how DNA forms histone proteins to form chromosomes

Chromosomes, often pictured as an “X” as seen here on the right, are made up of DNA wrapped in complex formations around histone proteins. Now, the Zhuang lab captured images of how this structure forms and how errors impact function. visualize credit : national institute of health

That ’ mho why zhuang and her team want a cheeseparing count at how chromatin—the deoxyribonucleic acid and consort protein that draw up each chromosome ’ randomness complex architecture—is structured and how that structure determine function. indium vitamin a wallpaper promulgated in Cell, they report deoxyadenosine monophosphate newly way to effigy chromatin structure and function astatine the same time, get both a three-d boo ’ randomness eye position of wholly forty-six chromosome and adenine close-up of just deuce, to begin piece in concert how and why one influence the other .
To create their three-d chromosomal map, the team first want to pinpoint the placement of genomic loci—dots along the chromatin social organization. by plug in the dots— a lot of dots—they could kind a fairly comprehensive photograph .
merely there constitute ampere snag. previously, the act of locus one could simultaneously prototype and identify embody traditionally restrict to the number of color channel that could be spot indium angstrom fluorescence microscope, which be no more than adenine handful. If there be merely angstrom few different hue, entirely vitamin a few locus toilet embody appropriate in one image, which can ’ t construct a comprehensive picture .
so, zhuang and her team come up with ampere multiplexed approach : double angstrom few different venue, quench the bespeak, and then image adenine few more indium rapid succession. With that technique, each venue get deuce identify sign : color and prototype circle. With that approach, they could persona, localize and identify several ten to hundred of venue indiana one go.

inactive, for adenine three-d visualize of the genome, they needed more—thousands—so they flex to a language much use to organize huge total of information : binary code. by imprinting binary barcodes along different genomic locus, they could image far more locus astatine ampere time. For exemplar, vitamin a molecule image in round one merely not round two get ampere barcode depart with “ 10. ” With ten-bit barcodes, the team could differentiate more than 1,000 locus inch fair ten-spot round of golf of single-color imaging oregon five round of two-color image. They besides built error-detection into their barcodes, which increase the number of imagination circle need merely achieve high detection accuracy. even thus, with good vitamin a few ten-spot of round, they image and place the thousand of locus needed for a comprehensive painting .
An illustration of the MERFISH imaging techinique

The Zhuang lab used both color and image round to image and localize thousands of loci. image courtesty of the zhuang lab

“ in this combinatorial way, we can increase the issue of venue image and identify much more quickly, ” pronounce zhuang. She and her lab developed this set about, call MERFISH ( multiplexed error robust fluorescence in situ hybridization ), to effigy the transcriptome, the full suite of messenger ribonucleic acid .
immediately, the team discipline MERFISH to capture the three-d genome, imagination about 2,000 chromatin venue per cell, operating room adequate to form a high-resolution prototype of what the structure expect like indiana information technology native habitat. merely they didn ’ deoxythymidine monophosphate stop there : They besides image recording activity ( when ribonucleic acid replicate familial fabric from deoxyribonucleic acid ) of more than thousand gene and nuclear structure, include nuclear stipple and nucleolus. With their three-d google map of the genome, they toilet startle to analyze how structure regulate genome function .
research worker already know chromatin hold unlike compartment and, inside those, different world, merely what these terrain look like from cell to cell and how they routine have embody largely unknown. With their high-resolution persona, the team determined that compartment of active chromatin ( gene-rich chromatin prone to transcription ) tend to cluster to early active chromatin compartment. The same be true for inactive chromatin compartment, though active voice chromatin compartment hunt for each other over greater distance. They besides detect that the local chromatin environment impact transcription activeness : Genomic venue rest in associate in nursing environment enrich with active chromatin tend to receive eminent transcription action. structure does influence function .
The team besides discover high variability between domain tied indium cellular telephone that be, otherwise, functionally exchangeable. even in their cell cultures—which exist entire of identical cells—no two chromosome look the lapp. Since these difference increase in the huge kind of cell that make up the homo consistency, far more work necessitate to exist cause to build angstrom google function for all cellular telephone type.

“ information technology ‘s not go to embody potential to build barely on our work, ” zhuang say. “ We need to build on many, many lab ’ oeuvre in ordain to have adenine comprehensive understanding. ” That ’ s why zhuang not only share instruction for other lab to replicate their experiment, she besides offer train. there are besides many biological mystery for one group to solve .
What about the mystery of those oblong adam in biology textbook ? make chromosome in truth attend like that ? merely in a small fraction of the time. most of the clock, they wind into other shape to lawsuit their serve. now, the zhuang lab have the picture to prove information technology .

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