UMMS researchers answer century old question about 3D structure of mitotic chromosomes
PUBLIC RELEASE DATE:
7-Nov-2013
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Contact: Jim Fessenden james.fessenden@umassmed.edu 508-856-2000 University of Massachusetts Medical School
New evidence shows that chromosomes assemble into linearly organized, compressed chromatin loops during the metaphase stage of cell division
WORCESTER, MA Using three dimensional modeling techniques, advanced computer simulation and next generation sequencing technology, faculty at the University of Massachusetts Medical School (UMMS) and the Massachusetts Institute of Technology (MIT) have resolved a long-standing debate that has consumed scientists ever since chromosomes were first observed under the light microscope by Walther Flemming in 1878.
In an article that appears in the online edition of Science, UMMS Professor Job Dekker, PhD, and colleagues show new evidence for a general principal of condensed, mitotic chromosome organization and structure that is highly adaptable and common to all cells. This new insight into how chromosomes are disassembled and reassembled during cell division will allow researchers to begin answering basic questions about epigenetic inheritance, as well as human disease such as chromosome disorders and cancer.
"Over the last several decades there have been conflicting theories for how the DNA is organized inside these chromosomes," said Dr. Dekker, co-director of the Program in Systems Biology at UMMS and senior author of the Science study. "We now have a model that incorporates this seemingly contradictory data and points to a single and simple process for condensed chromosome organization across all cell types. With this knowledge, we can begin asking very specific questions about how inheritance works and what happens when the process goes awry."
One of the most widely recognized biological structures in the cell, the tightly wound and elongated chromosome with its classic X-shaped structure can be easily discerned under a microscope and has been a common image in text books and popular scientific literature for decades. Despite this prevalence, technical limitations in microscopic studies have led to competing models for how the DNA is organized inside these chromosomes.
In its normal state, a cell's DNA is distributed in the cell nucleus over a relatively large area. Previous work from Dekker and colleagues had shown that points of interaction along the chromosome influence gene expression and are the reason why different cell types are organized differently in three dimensions. But in order to separate and be distributed successfully to each daughter cell, the chromosomes need to be tightly condensed and neatly packaged for transport and transmission to daughter cells.
One set of theories posed that the long DNA molecules are coiled up hierarchically into successively thicker fibers to ultimately form the sausage-like mitotic chromosomes. An alternate set of models proposed that the DNA forms a series of loops that are then attached to a linear axial structure that forms the backbone of the chromosome.
Different lines of experimental evidence supported both models, preventing ruling either theory in or out. In order to isolate the 3D structure of the chromosome during metaphase, the authors used a combination of chromosome conformation capture technologies (3C, 5C and Hi-C) developed by the Dekker lab over the last decade to map the points of contact along the mitotic chromosome in different cell types synchronized to divide at the same time. The complex sets of data this yielded provided the backbone for understanding the three dimensional structure and spatial organization of these chromosomes.
Next, Dekker and the team, led by Leonid Mirny, PhD, associate professor at the Massachusetts Institute of Technology, developed sophisticated computer simulations using polymer models of the DNA molecule for the two competing theories for mitotic chromosome organization. Plugging each model into the simulation, Dekker, Mirny and colleagues found that their chromosome conformation capture data was inconsistent with the classical, hierarchical model. Instead, they found that during metaphase the chromosome was being packaged in a two phase process. In the first phase, chromatin loops of 80,000 to 120,000 DNA base pairs form, radiating out from a scaffold and compacting the chromosome linearly. This was followed by axial compression of the chromosome, much like a spring being compressed, resulting in a neat, tightly folded package.
"Each cell type, whether blood, skin or liver cell, has a unique structure and organization that is closely tied to gene expression and function," said Dekker. "When the cell begins to divide that structure is disassembled. The specific patterns or organization tied to cell type are stripped away and the universal mitotic chromosome is formed. The process results in each cell being condensed and repackaged in a way that is common across cells types and points to a fundamental process of cell biology."
"When you look at the condensed chromosome it appears to be highly organized," said Dekker. "But the truth is that the process is very variable and adaptable because these chromatin loops form randomly along the chromosomes, which makes the process incredibly robust and adaptable."
Natalia Naumova, PhD, a postdoctoral fellow at UMMS and one of the lead authors of the study said, "We didn't expect that the chromosome would be organized this way. This stochastic process, which is locally random, results more globally in a high degree of stability and robustness, which is needed for cells to divide successfully."
The next step for Dekker, Mirny and their teams is to determine what, precisely, is guiding the disassembling and reassembling of the chromosome. "Because most transcription largely ceases in mitosis, and many proteins dissociate from the chromosome, something has to be responsible for reassembling chromosomes after cell division according to their cell type. Understanding the organization of the mitotic chromosome will help to understand how things go wrong in disease caused by chromosome disorder such as cancer or Down syndrome."
###
About the University of Massachusetts Medical School
The University of Massachusetts Medical School (UMMS), one of five campuses of the University system, is comprised of the School of Medicine, the Graduate School of Biomedical Sciences, the Graduate School of Nursing, a thriving research enterprise and an innovative public service initiative, Commonwealth Medicine. Its mission is to advance the health of the people of the Commonwealth through pioneering education, research, public service and health care delivery with its clinical partner, UMass Memorial Health Care. In doing so, it has built a reputation as a world-class research institution and as a leader in primary care education. The Medical School attracts more than $240 million annually in research funding, placing it among the top 50 medical schools in the nation. In 2006, UMMS's Craig C. Mello, PhD, Howard Hughes Medical Institute Investigator and the Blais University Chair in Molecular Medicine, was awarded the Nobel Prize in Physiology or Medicine, along with colleague Andrew Z. Fire, PhD, of Stanford University, for their discoveries related to RNA interference (RNAi). The 2013 opening of the Albert Sherman Center ushered in a new era of biomedical research and education on campus. Designed to maximize collaboration across fields, the Sherman Center is home to scientists pursuing novel research in emerging scientific fields with the goal of translating new discoveries into innovative therapies for human diseases.
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UMMS researchers answer century old question about 3D structure of mitotic chromosomes
PUBLIC RELEASE DATE:
7-Nov-2013
[
| E-mail
]
Share
Contact: Jim Fessenden james.fessenden@umassmed.edu 508-856-2000 University of Massachusetts Medical School
New evidence shows that chromosomes assemble into linearly organized, compressed chromatin loops during the metaphase stage of cell division
WORCESTER, MA Using three dimensional modeling techniques, advanced computer simulation and next generation sequencing technology, faculty at the University of Massachusetts Medical School (UMMS) and the Massachusetts Institute of Technology (MIT) have resolved a long-standing debate that has consumed scientists ever since chromosomes were first observed under the light microscope by Walther Flemming in 1878.
In an article that appears in the online edition of Science, UMMS Professor Job Dekker, PhD, and colleagues show new evidence for a general principal of condensed, mitotic chromosome organization and structure that is highly adaptable and common to all cells. This new insight into how chromosomes are disassembled and reassembled during cell division will allow researchers to begin answering basic questions about epigenetic inheritance, as well as human disease such as chromosome disorders and cancer.
"Over the last several decades there have been conflicting theories for how the DNA is organized inside these chromosomes," said Dr. Dekker, co-director of the Program in Systems Biology at UMMS and senior author of the Science study. "We now have a model that incorporates this seemingly contradictory data and points to a single and simple process for condensed chromosome organization across all cell types. With this knowledge, we can begin asking very specific questions about how inheritance works and what happens when the process goes awry."
One of the most widely recognized biological structures in the cell, the tightly wound and elongated chromosome with its classic X-shaped structure can be easily discerned under a microscope and has been a common image in text books and popular scientific literature for decades. Despite this prevalence, technical limitations in microscopic studies have led to competing models for how the DNA is organized inside these chromosomes.
In its normal state, a cell's DNA is distributed in the cell nucleus over a relatively large area. Previous work from Dekker and colleagues had shown that points of interaction along the chromosome influence gene expression and are the reason why different cell types are organized differently in three dimensions. But in order to separate and be distributed successfully to each daughter cell, the chromosomes need to be tightly condensed and neatly packaged for transport and transmission to daughter cells.
One set of theories posed that the long DNA molecules are coiled up hierarchically into successively thicker fibers to ultimately form the sausage-like mitotic chromosomes. An alternate set of models proposed that the DNA forms a series of loops that are then attached to a linear axial structure that forms the backbone of the chromosome.
Different lines of experimental evidence supported both models, preventing ruling either theory in or out. In order to isolate the 3D structure of the chromosome during metaphase, the authors used a combination of chromosome conformation capture technologies (3C, 5C and Hi-C) developed by the Dekker lab over the last decade to map the points of contact along the mitotic chromosome in different cell types synchronized to divide at the same time. The complex sets of data this yielded provided the backbone for understanding the three dimensional structure and spatial organization of these chromosomes.
Next, Dekker and the team, led by Leonid Mirny, PhD, associate professor at the Massachusetts Institute of Technology, developed sophisticated computer simulations using polymer models of the DNA molecule for the two competing theories for mitotic chromosome organization. Plugging each model into the simulation, Dekker, Mirny and colleagues found that their chromosome conformation capture data was inconsistent with the classical, hierarchical model. Instead, they found that during metaphase the chromosome was being packaged in a two phase process. In the first phase, chromatin loops of 80,000 to 120,000 DNA base pairs form, radiating out from a scaffold and compacting the chromosome linearly. This was followed by axial compression of the chromosome, much like a spring being compressed, resulting in a neat, tightly folded package.
"Each cell type, whether blood, skin or liver cell, has a unique structure and organization that is closely tied to gene expression and function," said Dekker. "When the cell begins to divide that structure is disassembled. The specific patterns or organization tied to cell type are stripped away and the universal mitotic chromosome is formed. The process results in each cell being condensed and repackaged in a way that is common across cells types and points to a fundamental process of cell biology."
"When you look at the condensed chromosome it appears to be highly organized," said Dekker. "But the truth is that the process is very variable and adaptable because these chromatin loops form randomly along the chromosomes, which makes the process incredibly robust and adaptable."
Natalia Naumova, PhD, a postdoctoral fellow at UMMS and one of the lead authors of the study said, "We didn't expect that the chromosome would be organized this way. This stochastic process, which is locally random, results more globally in a high degree of stability and robustness, which is needed for cells to divide successfully."
The next step for Dekker, Mirny and their teams is to determine what, precisely, is guiding the disassembling and reassembling of the chromosome. "Because most transcription largely ceases in mitosis, and many proteins dissociate from the chromosome, something has to be responsible for reassembling chromosomes after cell division according to their cell type. Understanding the organization of the mitotic chromosome will help to understand how things go wrong in disease caused by chromosome disorder such as cancer or Down syndrome."
###
About the University of Massachusetts Medical School
The University of Massachusetts Medical School (UMMS), one of five campuses of the University system, is comprised of the School of Medicine, the Graduate School of Biomedical Sciences, the Graduate School of Nursing, a thriving research enterprise and an innovative public service initiative, Commonwealth Medicine. Its mission is to advance the health of the people of the Commonwealth through pioneering education, research, public service and health care delivery with its clinical partner, UMass Memorial Health Care. In doing so, it has built a reputation as a world-class research institution and as a leader in primary care education. The Medical School attracts more than $240 million annually in research funding, placing it among the top 50 medical schools in the nation. In 2006, UMMS's Craig C. Mello, PhD, Howard Hughes Medical Institute Investigator and the Blais University Chair in Molecular Medicine, was awarded the Nobel Prize in Physiology or Medicine, along with colleague Andrew Z. Fire, PhD, of Stanford University, for their discoveries related to RNA interference (RNAi). The 2013 opening of the Albert Sherman Center ushered in a new era of biomedical research and education on campus. Designed to maximize collaboration across fields, the Sherman Center is home to scientists pursuing novel research in emerging scientific fields with the goal of translating new discoveries into innovative therapies for human diseases.
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In the documents, the 23-year-old asks for as much time with his son as the 4-year-old's mother. However, Bristol responded claiming that he owes $66,000 in child support, hinting that the request is financially motivated.
Back in 2008, the pair experienced happy times, announcing both their engagement and her pregnancy during the presidential election. Young love didn't last, though, and the two broke off their engagement in December 2008, reunited, then called it quits in August 2010. Since then, Levi married Sunny Oglesby.
Outraged at claims by In Touch magazine that he "abandoned" Suri after his divorce, Tom Cruise opened up about their relationship in a deposition filed as part of his $50 million lawsuit against the publisher.
During the interrogation, the "Mission Impossible" star was asked by Bauer Publishing attorneys to admit that he didn't see his daughter for over 100 days from August 4, 2012 until Thanksgiving.
Citing his filming schedule for "All You Need Is Kill" in London, the 50-year-old actor noted, "Unfortunately in this situation it was impossible."
However, he said he called the little girl almost daily, explaining, "you have to work at it. I've gotten very good at it. I tell wonderful stories. I also find that, you know, Suri is a very happy child, and confident, and has a good sense of herself."
Asked about other situations where he was invited to visit, Tom shared, "Things change and there is different agreements, like in any divorce, where you work out schedules. It's just a different set of circumstances. It certainly does not mean that I've abandoned my daughter." As an interesting note, the high-profile Scientologist did admit that Suri was no longer practicing the controversial religion.
WASHINGTON (AP) — Insurance cancellations are fueling a political backlash against President Barack Obama and Democrats supporting his health care overhaul.
The president apologized Thursday for the turmoil some consumers are going through, but there may yet be a silver lining as far as the law itself.
It's Economics 101, a little-noticed consequence of a controversial policy decision. And there are winners and losers.
Millions of people who currently buy their own health insurance coverage are losing it next year because their plans don't meet requirements of the health care law. But experts say the resulting shift of those people into the new health insurance markets under Obama's law would bring in customers already known to insurers, reducing the overall financial risks for each state's insurance pool.
That's painful for those who end up paying higher premiums for upgraded policies. But it could save money for the taxpayers who are subsidizing the new coverage.
"Already-insured people who do roll over will improve the risk pool, not hurt it," said David Axene, a California-based actuarial consultant for health plans, hospitals, government programs and employers.
Compared to the uninsured, people with coverage are less likely to have a pent-up need for medical services, he explained. They may have already had that knee replacement instead of hobbling around on a cane. They're also more likely to have seen a doctor regularly.
"The current individual market enrollees are definitely a good addition to the risk pool," concurred Larry Levitt, an insurance expert with the nonpartisan Kaiser Family Foundation.
At some point, all these customers had to pass extensive medical screening that insurers traditionally use to screen out people with health problems. Such filtering will no longer be allowed starting next year, and a sizable share of the uninsured people expected to gain coverage under Obama's law have health problems that has kept them from getting coverage. They'll be the costly cases.
Obama had sold his health care overhaul as a win all around. Uninsured Americans would get coverage and people with insurance could keep their plans if they liked them, he said. In hindsight, the president might have wanted to say that you could keep your plan as long as your insurer or your employer did not change it beyond certain limits prescribed by the government.
That test proved too hard for many plans purchased directly by individuals, leading to a wave of cancellations affecting at least 3.5 million people, based on an AP survey in which about half the states reported data.
"I am sorry that they ... are finding themselves in this situation, based on assurances they got from me," Obama said in an NBC interview, adding that the administration will do "everything we can" to help.
The new plans under Obama's law generally guarantee a broader set of basic benefits and provide stronger financial protection in cases of catastrophic illness.
"There is change coming to the individual marketplace with consumer protections that many people have never enjoyed or experienced," Health and Human Services Secretary Kathleen Sebelius told senators this week.
But better coverage also costs more.
"The loser is the consumer who is paying higher premiums to subsidize Obamacare, and who was paying lower premiums because they were in another plan before," said Bob Laszewski, a health care industry consultant critical of the law.
Ian Hodge of Lancaster, Pa., fears he'll lose out financially. He and his wife are in their early 60s, so Hodge said "we really don't worry about maternal care," one of the guaranteed benefits in the new plans. The Hodges recently got a cancellation notice and they're concerned a new plan may costs them hundreds of dollars more than they are paying now.
"We are the persons who President Obama wants to pay more in health care so we can subsidize some of the people who will pay less," said Hodge.
A new analysis backs up his instinct. The study by the Kaiser Family Foundation found that people who already have individual coverage, like the Hodges, are less likely to qualify for the tax credits that will make coverage more affordable through the health law's insurance markets.
According to the findings, 73 percent of potential customers who are uninsured will be eligible for tax credits that limit their premiums to a fixed percentage of their income. However, fewer than 40 percent of those who currently have individual health insurance will qualify.
In Congress, the Republican-controlled House is expected to vote next week on legislation permitting insurance companies to continue selling individual policies already in existence, even if they fall short of the law. The vote could pose a difficult choice to Democrats, who favor the law but also have been critical that it does not live up to Obama's pledge.
Separately, Senate legislation would provide for a one-year delay in the law's requirement for individuals to purchase insurance or pay a penalty. Under the measure, backed by Sens. Mark Kirk, R-Ill., and Joe Manchin, D-W. Va., that requirement would take effect on Jan. 1, 2015.
___
Associated Press writers David Espo in Washington and Michael Rubinkam in Allentown, Pa., contributed to this report.
She has no problem sharing her thoughts on Twitter, but Kylie Jenner may have stepped over the line with her recent comments about a specific mental illness.
On Wednesday (November 6), the "Keeping Up with the Kardashians" star posted an old pic donning her darker locks and added the caption, "I miss my black hair I'm so bipolar :(."
Unfortunately, the politically incorrect comment didn't sit too well with other Twitter users. One observer fired back with, "Kylie Jenner just tweeted 'I miss my black I'm so Bipolar :(' . No, you're not 'so Bipolar', you're indecisive... and a moron."
Another wrote, "That was 100% the dumbest and most ignorant use of the word bipolar."
Miss Jenner has yet to respond to the negative tweets at this time.
A joint research led by the Smithsonian Institution (US), Saint Louis University (US) and Universidad de Los Andes (Venezuela) resulted in the discovery of an exciting new species from the daisy family. The two expeditions in the paramos high up in the Venezuelan Andes were crowned by the discovery of the beautiful and extraordinary, Coespeletia palustris. The study was published in the open access journal Phytokeys.
The species of the genus Coespeletia are typical for high elevations and six of seven described species in total are endemic to the heights of the Venezuelan Andes; the 7th species comes from northern Colombia, but needs further revision according to the authors of the study. Most of the species are restricted to very high elevations, in a range between 38004800 m. The specifics of such habitat are believed to be the reason behind the peculiar and unrepeated pollen characteristics of the genus.
This new species Coespeletia palustris, is found in a few marshy areas of the paramo, and is endemic to the Venezuelan Andes. Pramo can refer to a variety of alpine tundra ecosystems, and is often described with its geographical confinements in the Andes. The pramo is the ecosystem of the regions above the continuous forest line, yet below the permanent snowline.
"Even after decades of studies and collections in the paramos, numerous localities remain unstudied." Explains Dr. Mauricio Diazgranados. "The new species described in this paper is called "palustris" because of the marshy habitat in which it grows. High elevation marshes and wetlands are among the ecosystems which are most impacted by climate change. Therefore this species may be at a certain risk of extinction as well."
###
Original Source:
Diazgranados M, Morillo G (2013) A new species of Coespeletia (Asteraceae, Millerieae) from Venezuela. PhytoKeys 28: 918. doi: 10.3897/phytokeys.28.6378
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Crown of Venezuelan paramos: A new species from the daisy family, Coespeletia palustris
A joint research led by the Smithsonian Institution (US), Saint Louis University (US) and Universidad de Los Andes (Venezuela) resulted in the discovery of an exciting new species from the daisy family. The two expeditions in the paramos high up in the Venezuelan Andes were crowned by the discovery of the beautiful and extraordinary, Coespeletia palustris. The study was published in the open access journal Phytokeys.
The species of the genus Coespeletia are typical for high elevations and six of seven described species in total are endemic to the heights of the Venezuelan Andes; the 7th species comes from northern Colombia, but needs further revision according to the authors of the study. Most of the species are restricted to very high elevations, in a range between 38004800 m. The specifics of such habitat are believed to be the reason behind the peculiar and unrepeated pollen characteristics of the genus.
This new species Coespeletia palustris, is found in a few marshy areas of the paramo, and is endemic to the Venezuelan Andes. Pramo can refer to a variety of alpine tundra ecosystems, and is often described with its geographical confinements in the Andes. The pramo is the ecosystem of the regions above the continuous forest line, yet below the permanent snowline.
"Even after decades of studies and collections in the paramos, numerous localities remain unstudied." Explains Dr. Mauricio Diazgranados. "The new species described in this paper is called "palustris" because of the marshy habitat in which it grows. High elevation marshes and wetlands are among the ecosystems which are most impacted by climate change. Therefore this species may be at a certain risk of extinction as well."
###
Original Source:
Diazgranados M, Morillo G (2013) A new species of Coespeletia (Asteraceae, Millerieae) from Venezuela. PhytoKeys 28: 918. doi: 10.3897/phytokeys.28.6378
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| E-mail
Share
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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.