Only two interchangeable ways of folding genomes into nuclei

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How precisely genomes ranging from a few million to billions of base pairs, several meters long, can fold into tiny cell nuclei, averaging 6 microns, is a bewildering conundrum. Yet the nuclear architecture at the chromosome level, although poorly understood, can play a crucial role in regulating gene expression in health and disease.

A new collaborative study investigates the principles of genome folding across the eukaryotic tree of life comprising 24 species, representing all taxonomic groups in chrordates and extant vertebrates that include animals, fungi and plants. Researchers use a method called in situ Hi-C that detects and quantifies pairwise interactions between chromosomal regions of a genome and digital simulations.

Their results show two types or states of three-dimensional genomic architectures at the chromosomal scale which appear and disappear several times during the evolution of nucleated organisms (eukaryotes) and are regulated by the presence of the protein condensin II.

Between cell divisions when the cell is in interphase, the authors show that telomeres (repeating sequences at the ends of linear chromosomes) and centromeres (specialized DNA sequences that link pairs of duplicated chromosomes, called chromatids) cluster together on the chromosomes, much like the center and edges of a newspaper, or orient themselves to maintain separate chromosome territories much like individual grapes in a bunch.

The authors also show that the removal of condensin II converts the 3D nuclear architecture of human genomes into one that resembles a mosquito.

The study, published in the journal Science in an article titled “3D Genomics Through the Tree of Life Reveals Condensin II as a Determinant of Architecture Type” arose out of the collaborative efforts of DNA Zoo, an international consortium spanning dozens of institutions, including Baylor College of Medicine, the National Science Foundation (NSF) supported the Center for Theoretical Biological Physics (CTBP) at Rice University, University of Western Australia and SeaWorld.

Olga Dudchenko, PhD, co-first author of the study

“Whether we were looking at worms or sea urchins, sea squirts or corals, we always saw the same folding patterns coming,” says Olga Dudchenko, PhD, co-first author of the new study and a member of the Center for Genome Architecture at Baylor and CTBP.

The team finally focused on two global nuclear architectures from this multispecies analysis.

“In some species, the chromosomes are organized like the pages of a printed newspaper, with the outer margins on one side and the middle folded on the other,” explained Dudchenko, who is also co-director of DNA Zoo. “In other species, each chromosome is crumpled into a little ball.”

Erez Lieberman Aiden, PhD, Associate Professor of Molecular and Human Genetics, McNair Distinguished Fellow at Baylor, Co-Director of DNA Zoo, Director of the Center for Genome Architecture, Principal Investigator at CTBP and Principal Author of the New Study

“We had a conundrum,” says Erez Lieberman Aiden, PhD, associate professor of molecular and human genetics, McNair researcher emeritus at Baylor, co-director of DNA Zoo, director of the Center for Genome Architecture, principal investigator at CTBP and lead author of the short story. study.

“The data implied that during evolution, species can switch from one type to another. We asked ourselves: what is the control mechanism? Would it be possible to change one type of nucleus to another in the laboratory? Aiden said.

Meanwhile, an independent team in the Netherlands was working on the role of condensin II in cell division.

“When we mutated the protein in human cells, the chromosomes would completely rearrange themselves. It was confusing! ”Says Claire Hoencamp, PhD, co-first author of the study and lab member of Benjamin Rowland, PhD, at the Dutch Cancer Institute.

Claire Hoencamp, PhD, co-first author of the study

Teams Rowland and Aiden met at a conference in the Austrian mountains where Rowland presented the latest work from his lab. By combining their data, the teams deduced that Hoencamp had converted human cells from one nuclear state to another by mutating condensin II.

“When we looked at the genomes studied at DNA Zoo, we found that evolution had already been our experience many, many times! When mutations in a species break condensin II, they usually reverse the entire architecture of the nucleus, ”said Rowland, lead author of the study. “It’s always a bit disappointing to be selected in an experiment, but evolution had a very long head start. “

Benjamin Rowland, PhD, Head of Chromosome Biology Group, Dutch Cancer Institute

The team decided to work together to confirm the role of Condensin II, but the COVID-19 pandemic has struck.

“Without access to our labs, we only had one way to find out what Condensin II was doing,” Hoencamp explains. “We needed to create a computer program that could simulate the effects of Condensin II on the chain of hundreds of millions of genetic letters that make up every human chromosome. “

To do this, the team turned to José Onuchic, PhD, holder of the Harry C. Physics Chair and Olga K. Wiess of Rice.

“Our simulations showed that by destroying condensin II, you could make a human nucleus reorganize itself to resemble a fly nucleus,” says Onuchic, co-director of CTBP, which includes collaborators from Rice, Baylor, Northeastern University and other institutions in Houston and Boston. .

Sumitabha Brahmachari, PhD, postdoctoral researcher and co-first author of Onuchic’s lab at CTBP, working with Vinicius Contessoto, PhD, former postdoctoral fellow at CTBP, and Michele Di Pierro, PhD, principal investigator at CTBP and currently assistant professor at CTBP Northeastern University, performed the simulations.

Brahmachari says, “We started with an incredibly large study of 2 billion years of nuclear evolution and found that it all comes down to a simple mechanism, which we can simulate as well as summarize, on our own, in a test tube. This is an exciting step on the road to a new type of genome engineering, in 3D! “


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