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  • richardmitnick 8:35 am on January 10, 2017 Permalink | Reply
    Tags: , , Leukemia - The key to self-destruction, , , or TADs, , Syndactyly, topologically associating domains   

    From NYT: “A Family’s Shared Defect Sheds Light on the Human Genome” 

    New York Times

    The New York Times

    JAN. 9, 2017
    NATALIE ANGIER

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    Headcase Design

    They said it was their family curse: a rare congenital deformity called syndactyly, in which the thumb and index finger are fused together on one or both hands. Ten members of the extended clan were affected, and with each new birth, they told Stefan Mundlos of the Max Planck Institute for Molecular Genetics, the first question was always: “How are the baby’s hands? Are they normal?”

    Afflicted relatives described feeling like outcasts in their village, convinced that their “strange fingers” repulsed everybody they knew — including their unaffected kin. “One woman told me that she never received a hug from her father,” Dr. Mundlos said. “He avoided her.”

    The family, under promise of anonymity, is taking part in a study by Dr. Mundlos and his colleagues of the origin and development of limb malformations. And while the researchers cannot yet offer a way to prevent syndactyly, or to entirely correct it through surgery, Dr. Mundlos has sought to replace the notion of a family curse with “a rational answer for their condition,” he said — and maybe a touch of pioneers’ pride.

    The scientists have traced the family’s limb anomaly to a novel class of genetic defects unlike any seen before, a finding with profound implications for understanding a raft of heretofore mysterious diseases.

    The mutations affect a newly discovered design feature of the DNA molecule called topologically associating domains, or TADs. It turns out that the vast informational expanse of the genome is divvied up into a series of manageable, parochial and law-abiding neighborhoods with strict nucleic partitions between them — each one a TAD.

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    The hand of a woman with syndactyly, the congenital fusion of fingers. The deformity may range from a slight degree of webbing to almost complete fusion as shown here. Credit SPL/Science Source

    Breach a TAD barrier, and you end up with the molecular equivalent of that famous final scene in Mel Brooks’s comedy, “Blazing Saddles,” when the cowboy actors from one movie set burst through a wall and onto the rehearsal stage of a campy Fred Astaire-style musical. Soon fists, top hats and cream pies are flying.

    By studying TADs, researchers hope to better fathom the deep structure of the human genome, in real time and three dimensions, and to determine how a quivering, mucilaginous string of some three-billion chemical subunits that would measure more than six-feet long if stretched out nonetheless can be coiled and compressed down to four-10,000ths of an inch, the width of a cell nucleus — and still keep its operational wits about it.

    “DNA is a super-long molecule packed into a very small space, and it’s clear that it’s not packed randomly,” Dr. Mundlos said. “It follows a very intricate and controlled packing mechanism, and TADs are a major part of the folding protocol.”

    For much of the past 50 years, genetic research has focused on DNA as a kind of computer code, a sequence of genetic “letters” that inscribe instructions for piecing together amino acids into proteins, which in turn do the work of keeping us alive.

    Read Between the Folds

    Most of the genetic diseases deciphered to date have been linked to mishaps in one or another protein recipe. Scanning the DNA of patients with Duchenne muscular dystrophy, for example, scientists have identified telltale glitches in the gene that encodes dystrophin, a protein critical to muscle stability.

    At the root of Huntington’s disease, which killed the folk singer Woody Guthrie, are short, repeated bits of nucleic nonsense sullying the code for huntingtin, an important brain protein. The mutant product that results soon shatters into neurotoxic shards.

    Yet researchers soon realized there was much more to the genome than the protein codes it enfolded. “We were caught up in the idea of genetic information being linear and one-dimensional,” said Job Dekker, a biologist at the University of Massachusetts Medical School.

    For one thing, as the sequencing of the complete human genome revealed, the portions devoted to specifying the components of hemoglobin, collagen, pepsin and other proteins account for just a tiny fraction of the whole, maybe 3 percent of human DNA’s three billion chemical bases.

    And there was the restless physicality of the genome, the way it arranged itself during cell division into 23 spindly pairs of chromosomes that could be stained and studied under a microscope, and then somehow, when cell replication was through, merged back together into a baffling, ever-wriggling ball of chromatin — DNA wrapped in a protective packaging of histone proteins.

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    Stefan Mundlos of the Max Planck Institute for Molecular Genetics in Germany studies the origin and development of limb malformations, some of which are caused by a novel class of genetic defects. Credit Norbert Michalke/Max Planck Institute for Molecular Genetics, Berlin

    What was the link, scientists wondered, between the shape and animation of the DNA molecule at any given moment, in any given cell — and every cell has its own copy of the genome — and the relative mouthiness or muteness of the genetic information the DNA holds?

    “We realized that in order to understand how genetic information is controlled, we had to figure out how DNA was folded in space,” said Bing Ren of the University of California, San Diego.

    Using a breakthrough technology developed by Dr. Dekker and his colleagues called chromosome conformation capture, researchers lately have made progress in tracking the deep structure of DNA. In this approach, chromatin is chemically “frozen” in place, enzymatically chopped up and labeled, and then allowed to reassemble.

    The pieces that find each other again, scientists have determined, are those that were physically contiguous in the first place — only now all their positions and relationships are clearly marked.

    Through chromosome conformation studies and related research, scientists have discovered the genome is organized into about 2,000 jurisdictions, and they are beginning to understand how these TADs operate.

    As with city neighborhoods, TADs come in a range of sizes, from tiny walkable zones a few dozen DNA subunits long to TADs that sprawl over tens of thousands of bases and you’re better off taking the subway. TAD borders serve as folding instructions for DNA. “They’re like the dotted lines on a paper model kit,” Dr. Dekker said.

    TAD boundaries also dictate the rules of genetic engagement.

    Scientists have long known that protein codes are controlled by an assortment of genetic switches and enhancers — noncoding sequences designed to flick protein production on, pump it into high gear and muzzle it back down again. The new research indicates that switches and enhancers act only on those genes, those protein codes, stationed within their own precincts.

    Because TADs can be quite large, the way the Upper West Side of Manhattan comprises an area of about 250 square blocks, a genetic enhancer located at the equivalent of, say, Lincoln Center on West 65th Street, can amplify the activity of a gene positioned at the Cathedral of St. John the Divine, 45 blocks north.

    But under normal circumstances, one thing an Upper West Side enhancer will not do is reach across town to twiddle genes residing on the Upper East Side.

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    Scientists have learned that disruptions of the genome’s boundaries may cause syndactyly and other diseases, including some pediatric brain disorders that affect the brain’s white matter. Credit Living Art Enterprises, LLC/Science Source

    “Genes and regulatory elements are like people,” Dr. Dekker said. “They care about and communicate with those in their own domain, and they ignore everything else.”

    Breaking Boundaries

    What exactly do these boundaries consist of, that manage to both direct the proper folding of the DNA molecule and prevent cross talk between genes and gene switches in different domains? Scientists are not entirely sure, but preliminary results indicate that the boundaries are DNA sequences that attract the attention of sticky, roughly circular proteins called cohesin and CTCF, which adhere thickly to the boundary sequences like insulating tape.

    Between those boundary points, those clusters of insulating proteins, the chromatin strand can loop up and over like the ribbon in a birthday bow, allowing genetic elements distributed along the ribbon to touch and interact with one another. But the insulating proteins constrain the movement of each chromatin ribbon, said Richard A. Young of the Whitehead Institute for Biomedical Research, and keep it from getting entangled with neighboring loops — and the genes and regulatory elements located thereon.

    The best evidence for the importance of TADs is to see what happens when they break down. Researchers have lately linked a number of disorders to a loss of boundaries between genomic domains, including cancers of the colon, esophagus, brain and blood.

    In such cases, scientists have failed to find mutations in any of the protein-coding sequences commonly associated with the malignancies, but instead identified DNA damage that appeared to shuffle around or eliminate TAD boundaries. As a result, enhancers from neighboring estates suddenly had access to genes they were not meant to activate.

    Reporting in the journal Science, Dr. Young and his colleagues described a case of leukemia in which a binding site for insulator proteins had been altered not far from a gene called TAL1, which if improperly activated is known to cause leukemia. In this instance, disruption of the nearby binding site, Dr. Young said, “broke up the neighborhood and allowed an outside enhancer to push TAL1 to the point of tumorigenesis,” the production of tumors.

    Now that researchers know what to look for, he said, TAD disruptions may prove to be a common cause of cancer. The same may be true of developmental disorders — like syndactyly.

    In journals like Cell and Nature, Dr. Mundlos and his co-workers described their studies of congenital limb malformations in both humans and mice. The researchers have detected major TAD boundary disruptions that allowed the wrong control elements to stimulate muscle genes at the wrong time and in the wrong tissue.

    “If a muscle gene turns on in the cartilage of developing digits,” Dr. Mundlos said, “you get malformations.”

    Edith Heard, director of the genetics and developmental biology department at the Institut Curie in France, who with Dr. Dekker coined the term TAD, said that while researchers were just beginning to get a handle on the architecture of DNA, “suddenly a lot of things are falling into place. We’re coming into a renaissance time for understanding how the genome works.”

    See the full article here .

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  • richardmitnick 7:20 am on July 15, 2016 Permalink | Reply
    Tags: , Leukemia - The key to self-destruction,   

    From TUM- Leukemia:”The key to self-destruction” 

    Techniche Universitat Munchen

    Techniche Universitat Munchen

    14.07.2016
    PD Dr. Philipp J. Jost
    III. Medizinische Klinik und Poliklinik
    Klinikum rechts der Isar
    Technical University of Munich
    Tel: +49 (89) 4140-5941
    philipp.jost@tum.de

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    In Cancer Cell Ulrike Höckendorf and Dr. Philipp Jost describe a new molecular signaling pathway for self-destruction that is suppressed in leukemia cells. (Foto: Heddergott / TUM)

    When adults develop blood cancer, they are frequently diagnosed with what is referred to as acute myeloid leukemia. The disease is triggered by pathological alterations of bone marrow cells, in which, in addition, an important mechanism is out of action: these cells do not die when they are damaged. Researchers from the Technical University of Munich (TUM) have now discovered a molecular signaling pathway for self-destruction that is suppressed in leukemia cells.

    Leukemia involves pathological alterations in the body’s hematopoietic system. In acute myeloid leukemia, it is specifically the bone marrow (Greek: myelos) that is affected. In a healthy body, different blood cells, which perform different functions in the blood, are formed from stem cells and what is referred to as progenitor cells in the bone marrow. A genetic mutation can lead to alterations in stem cells and progenitor cells and turn them into leukemia-initiating cells, which are referred to as LICs for short. Like healthy progenitor cells, LICs multiply in the bone marrow. The genetic mutation, however, causes LICs to remain without function and prevents them from developing into mature blood cells, which ultimately leads to the repression of healthy hematopoiesis in the bone marrow and the onset of leukemia symptoms.

    The most frequent genetic alterations in myeloid leukemia include mutations in the FLT3 gene. A team led by Dr. Philipp Jost from the Department of Hematology/Oncology at Klinikum rechts der Isar at the Technical University of Munich has now discovered that the effects of this gene on pathologically altered cells in a way provide certain indications for the treatment of the disease. The mutation causes a permanent activation of the FLT3 gene. As demonstrated by the scientists, this triggers inflammation-like stimuli in the cell, subjecting it to permanent stress.

    Growth despite inflammation and damage

    Under normal circumstances, such permanent inflammatory stimuli would trigger a program known as programmed cell death to replace damaged cells. This is a kind of self-destruction mechanism used by a cell to initiate its own destruction in a coordinated fashion and allow it to be replaced by a healthy one. “By contrast, LICs manage to grow and proliferate despite the inflammation and damage,” states Philipp Jost. “In our study, we have taken a closer look at the molecular causes of this resistance.”

    To gain a better understanding of the research project described by the TUM scientists in the medical journal Cancer Cell, it is important to understand that cells have different ways of self-destructing. So far, the primary research focus in trying to ascertain why cancer cells survive longer than they should has been placed on a process called apoptosis. However, the fact that inflammatory processes occur in LICs pointed Philipp Jost and his colleagues in a different direction. Another way to initiate cell death is through what is referred to as necroptosis. Whereas, in apoptosis, a cell shrinks in a coordinated fashion, in necroptosis, a sudden destruction occurs, which releases the contents of the dying cell along with numerous messenger substances. This induces a strong inflammatory stimulus in the vicinity of the cell.

    Cancer cells block activation of protein

    Necroptosis is triggered by the activation of a protein called RIPK3, which subsequently initiates processes within the cell that lead to its death. The scientists used cell cultures to discover that leukemia takes a particularly severe course when RIPK3 is blocked inside LICs. This led to the cancer cells surviving particularly long, accompanied by their strong division and conversion to functionless blood cells (blasts). “We conclude from our findings that particularly aggressive cancer cells have the capacity to block RIPK3,” states Ulrike Höckendorf, lead author of the study. “Exactly how they accomplish this, however, remains to be investigated.”
    Inducing cell death in a LIC by means of necroptosis has repercussions which also affect neighboring leukemia cells. The inflammatory stimuli triggered by the substances released during necroptosis are significantly stronger than the processes caused by the mutation in the FLT3 gene in a LIC. This inflammation has positive effects on the area surrounding the cell: induced by the messenger substances, neighboring leukemia cells begin to mature similar to healthy cells, leading to a less aggressive progression of leukemia.

    With cell death blocked – apoptosis, too, is “neutralized” in many cancer cells – individual LICs manage to survive and proliferate even after chemotherapy or radiotherapy. “The new findings on the impact of the RIPK3 signaling pathway and the messenger substances released could open up new options for the treatment of leukemia,” states Philipp Jost. “If it were possible to artificially reproduce the effect of RIPK3 using medication, one could launch a targeted attack on leukemia cells.”

    Original Publication

    U. Höckendorf, Mo. Yabal, T. Herold, E. Munkhbaatar, S. Rott, S. Jilg, J. Kauschinger, G. Magnani, F. Reisinger, M. Heuser, H. Kreipe, K.Sotlar, T. Engleitner, R. Rad, W. Weichert, C. Peschel, J. Ruland, M. Heikenwalder, K. Spiekermann, J. Slotta-Huspenina, O. Groß, P. Jost. RIPK3 Restricts Myeloid Leukemogenesis by Promoting Cell Death and Differentiation of Leukemia Initiating Cells. Cancer Cell Vol. 30:1 (2016). DOI: 10.1016/j.ccell.2016.06.002

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Techniche Universitat Munchin Campus

    Technische Universität München (TUM) is one of Europe’s top universities. It is committed to excellence in research and teaching, interdisciplinary education and the active promotion of promising young scientists. The university also forges strong links with companies and scientific institutions across the world. TUM was one of the first universities in Germany to be named a University of Excellence. Moreover, TUM regularly ranks among the best European universities in international rankings.

     
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