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Scientists Clarify a Mechanism of Epigenetic Inheritance
April 23, 2008Although letters representing the three billion pairs of molecules that form the "rungs" of the helical DNA "ladder" are routinely called the human "genetic code," the DNA they comprise transmits traits across generations in a variety of ways, not all of which depend on the sequence of letters in the code.
In some cases, rather than the sequence of "letters," it is the physical manner in which DNA is spun around protein spools called histones and tightly packed into chromosomes that determines whether or with what intensity specific genes are expressed. A team of scientists at Cold Spring Harbor Laboratory (CSHL) has solved another in a series of mysteries about this critical mechanism of gene expression, described in a paper in the April 8 issue of Current Biology.
Inherited Clumping
According to CSHL professor Rob Martienssen, Ph.D., who led the research team, about a tenth of our DNA stands aloof, spending its time in tightly packed clumps called heterochromatin, and unwinding only to replicate when a cell divides. After copying, both of the resulting DNA molecules - to the surprise of many - have been observed to form reclusive clumps in the same places as the original one did.
This inherited clumping of DNA, which causes genes to be expressed in distinctive ways, is one of a series of phenomena that scientists call epigenetic. The same sequence of nucleotides in two people can produce different patterns of gene expression if the way the DNA is clumped happens to be different.
Probing Epigenetics in Yeast
"We have not understood epigenetic inheritance very well," says Dr. Martienssen, a plant geneticist and one of the pioneers in the study of epigenetics. To explore this process, he and his team are studying the way DNA is packed in yeast, and how this packing can be transmitted across generations. The single-cell yeast organism is easy to study, in part because it lacks other epigenetic inheritance mechanisms, such as chemical modifications of DNA, that complicate the study of more complex animals and plants.
Long DNA molecules almost miraculously cram into cell nuclei that are almost a million times smaller than they are. They do so by wrapping around proteins called histones, which array themselves along the length of the DNA molecule like beads on a string. These DNA-wrapped histones then form larger arrays. The densely packed mass is then modified chemically by other proteins to form heterochromatin.
The dense packing of heterochromatin hides the DNA sequence from the cellular machinery that reads its genetic information, so the DNA in heterochromatin is "silenced." The genes it contains are effectively turned off.
Surprisingly, the clumping persists even after cells divide, although, says Dr. Martienssen, "it's always been a mystery how modifications of histones could be inherited." A few years ago, however, his group and others solved this mystery. They found that histone modification is controlled by complicated cellular mechanisms broadly known as RNA interference, or RNAi.
In RNAi, RNA that is copied from particular regions of DNA interacts with various proteins to modify histones in the same regions. Because the RNA matches only the section of DNA that produced it, it "provides the specificity that you need to make sure that only that part of the chromosome gets these histone modifications," Dr. Martienssen says. "If the whole chromosome were to get those histone modifications, you'd be dead."
All in the Timing
These results raised a new puzzle, though: Since genes contained within heterochromatin are silenced, how can they give rise to the RNA molecules that help to modify histones? In new research, Martienssen's team has now solved this puzzle by tracking the cells through their cycle of growth and division.
They found that the interfering RNA molecules appear only during the brief part of the cell cycle when DNA is replicating. This result, Martienssen says, "neatly accounts for the paradox about how 'silent' heterochromatin can be transcribed [into interfering RNA], because it's transcribed only in a narrow window of the cell cycle."
The researchers also found that RNAi varies strongly with temperature. They speculate that this variation is responsible for inherited traits such as vernalization, the well-known process by which certain plants must be exposed to low temperatures before they will flower. Indeed, Martienssen says, there is "a whole slew of epigenetic phenomena that are sensitive to temperature."
"RNA Interference Guides Histone Modification during the S Phase of Chromosomal Replication" appears in the April 8, 2008, edition of Current Biology. The complete citation is as follows: Anna Kloc, Mikel Zaratiegui, Elphege Nora and Rob Martienssen. The paper is available online at:
http://www.current-biology.com/content/article/abstract?uid=PIIS0960982208003163.
Cold Spring Harbor Laboratory is a private, nonprofit research and education institution dedicated to exploring molecular biology and genetics in order to advance the understanding and ability to diagnose and treat cancers, neurological diseases and other causes of human suffering.
Cold Spring Harbor Laboratory
According to CSHL professor Rob Martienssen, Ph.D., who led the research team, about a tenth of our DNA stands aloof, spending its time in tightly packed clumps called heterochromatin, and unwinding only to replicate when a cell divides. After copying, both of the resulting DNA molecules - to the surprise of many - have been observed to form reclusive clumps in the same places as the original one did.
This inherited clumping of DNA, which causes genes to be expressed in distinctive ways, is one of a series of phenomena that scientists call epigenetic. The same sequence of nucleotides in two people can produce different patterns of gene expression if the way the DNA is clumped happens to be different.
Probing Epigenetics in Yeast
"We have not understood epigenetic inheritance very well," says Dr. Martienssen, a plant geneticist and one of the pioneers in the study of epigenetics. To explore this process, he and his team are studying the way DNA is packed in yeast, and how this packing can be transmitted across generations. The single-cell yeast organism is easy to study, in part because it lacks other epigenetic inheritance mechanisms, such as chemical modifications of DNA, that complicate the study of more complex animals and plants.
Long DNA molecules almost miraculously cram into cell nuclei that are almost a million times smaller than they are. They do so by wrapping around proteins called histones, which array themselves along the length of the DNA molecule like beads on a string. These DNA-wrapped histones then form larger arrays. The densely packed mass is then modified chemically by other proteins to form heterochromatin.
The dense packing of heterochromatin hides the DNA sequence from the cellular machinery that reads its genetic information, so the DNA in heterochromatin is "silenced." The genes it contains are effectively turned off.
Surprisingly, the clumping persists even after cells divide, although, says Dr. Martienssen, "it's always been a mystery how modifications of histones could be inherited." A few years ago, however, his group and others solved this mystery. They found that histone modification is controlled by complicated cellular mechanisms broadly known as RNA interference, or RNAi.
In RNAi, RNA that is copied from particular regions of DNA interacts with various proteins to modify histones in the same regions. Because the RNA matches only the section of DNA that produced it, it "provides the specificity that you need to make sure that only that part of the chromosome gets these histone modifications," Dr. Martienssen says. "If the whole chromosome were to get those histone modifications, you'd be dead."
All in the Timing
These results raised a new puzzle, though: Since genes contained within heterochromatin are silenced, how can they give rise to the RNA molecules that help to modify histones? In new research, Martienssen's team has now solved this puzzle by tracking the cells through their cycle of growth and division.
They found that the interfering RNA molecules appear only during the brief part of the cell cycle when DNA is replicating. This result, Martienssen says, "neatly accounts for the paradox about how 'silent' heterochromatin can be transcribed [into interfering RNA], because it's transcribed only in a narrow window of the cell cycle."
The researchers also found that RNAi varies strongly with temperature. They speculate that this variation is responsible for inherited traits such as vernalization, the well-known process by which certain plants must be exposed to low temperatures before they will flower. Indeed, Martienssen says, there is "a whole slew of epigenetic phenomena that are sensitive to temperature."
"RNA Interference Guides Histone Modification during the S Phase of Chromosomal Replication" appears in the April 8, 2008, edition of Current Biology. The complete citation is as follows: Anna Kloc, Mikel Zaratiegui, Elphege Nora and Rob Martienssen. The paper is available online at:
http://www.current-biology.com/content/article/abstract?uid=PIIS0960982208003163.
Cold Spring Harbor Laboratory is a private, nonprofit research and education institution dedicated to exploring molecular biology and genetics in order to advance the understanding and ability to diagnose and treat cancers, neurological diseases and other causes of human suffering.
Cold Spring Harbor Laboratory
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Cornell researchers have discovered a genetic mechanism in fruit flies that prevents two closely related species from reproducing, a finding that offers clues to how species evolve.
A solution to Darwin's 'mystery of the mysteries' emerges from the dark matter of the genome
Biological species are often defined on the basis of reproductive isolation. Ever since Darwin pointed out his difficulty in explaining why crosses between two species often yield sterile or inviable progeny (for instance, mules emerging from a cross between a horse and a donkey), biologists have struggled with this question.
NYU School of Medicine pathology researchers solve another mystery in B lymphocyte development
A new study published online in Nature Immunology ahead of the June 2009 print issue has found that homologous immunoglobulin (lg) alleles pair up in the nucleus at stages that coincide with V(D)J recombination of the heavy and light chain (Igh and Igk) loci.
When every photon counts
The eyes of nocturnal mammals have very large numbers of highly-sensitive rod photoreceptors (the cell type responsible for night vision). They have to perceive light which is less than a millionth of the intensity of daylight.
CSHL researchers explain process by which cells 'hide' potentially dangerous DNA segments
The DNA in the 23 pairs of chromosomes in each of the billions of cells of the human body is so tightly packed that it would measure six feet in length if stretched end to end. A genome of this size can squeeze into a cell's tiny nucleus because it is compressed into highly condensed chromatin fibers by proteins called histones.
Roles of DNA packaging protein revealed by Einstein scientists
Scientists at Albert Einstein College of Medicine of Yeshiva University have found that a class of chromatin proteins is crucial for maintaining the structure and function of chromosomes and the normal development of eukaryotic organisms.
CSHL researchers map changing epigenetic modifications that enable transposons to run amok
Much like cancer cells, plant cells grown for a long time outside of their normal milieu, in culture dishes, have highly unstable genomes.
Stowers Institute's Workman Lab discovers novel histone demethylase protein complex
The Stowers Institute's Workman Lab has discovered a novel histone demethylase protein complex characterized in work published today in Molecular Cell.
Massive project reveals shortcomings of modern genome analysis
The sequencing and comparison of 12 fruit fly genomes -- the result of a massive collaboration of hundreds of scientists from more than 100 institutions in 16 countries -- has thrust forward researchers' understanding of fruit flies, a popular animal model in science.
Where Broken DNA is Repaired
Ionizing radiation, toxic chemicals, and other agents continually damage the body's DNA, threatening life and health: unrepaired DNA can lead to mutations, which in turn can lead to diseases like cancer.
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Heterochromatin: Webster's Timeline History, 1952 - 2007 by Icon Group International (Author) Webster's bibliographic and event-based timelines are comprehensive in scope, covering virtually all topics, geographic locations and people. They do so from a linguistic point of view, and in the case of this book, the focus is on "Heterochromatin," including when used in literature (e.g. all authors that might have Heterochromatin in their name). As such, this book represents the largest compilation of timeline events associated with Heterochromatin when it is used in proper noun form. Webster's timelines cover bibliographic citations, patented inventions, as well as non-conventional and alternative meanings which capture ambiguities in usage. These furthermore cover all parts of speech (possessive, institutional usage, geographic usage) and contexts, including pop culture, the arts,... |
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CHROMOSOMES OF ANTELOPE SQUIRRELS (GENUS AMMOSPERMOPHILUS): A SYSTEMATIC BANDING ANALYSIS OF FOUR SPECIES WITH UNUSUAL CONSTITUTIVE HETEROCHROMATIN. by J. & J. Mazrimas Mascarello (Author), Plates (Illustrator) | |
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Silencing, Heterochromatin and DNA Double Strand Break Repair by Kevin D. Mills (Author) The field of DNA repair is vast and advancing rapidly. Silencing, Heterochromatin and DNA Double Strand Break Repair probes the relationship of DNA break repair and silent heterochromatin, using budding yeast as a model. The primary research presented in this book represents some of the most important work in this new field of inquiry. |
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Heterochromatin: Molecular and Structural Aspects by Ram Sagar Verma (Editor) Ram Verma has assembled ten distinguished contributors to survey what is currently known about the relationship of the structure of DNA to its role in the function and expression of genes. The crucial role of heterochromatin in the organization of chromosomes is thoroughly explored in this resulting landmark edited volume. Cytogeneticists and other geneticists, molecular biologists, cytologists, biochemists and their advanced students will also find this an invaluable reference source. |
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RNA Interference (Current Topics in Microbiology and Immunology) by Patrick J. Paddison (Author), Patrick J. Paddison (Editor), Peter K. Vogt (Editor) In the last few years the major effect that RNAi has had in invertebrate systems like C.elegans and drosophila is beginning to take hold in mammalian systems through both single gene knockdown experiments and genome-scale screens. In the next decade, there will no doubt be both notable successes and failures as we attempt to apply this genetic tool to various biological problems for the first time in academia and industry. Through the introduction of RNAi, mammalian systems have finally gained admittance to the pantheon of model genetic systems. |
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Protein Complexes that Modify Chromatin. Current Topics in Microbiology and Immunology, No. 274 by Jerry L. Workman (Editor) This book provides timely reviews of several protein complexes that regulate gene expression and chromatin dynamics. Examples of such complexes include: nucleosome assembly complexes, ATP-dependent chromatin remodeling complexes, histone acetyltransferase complexes, histone deacetylase complexes, heterochromatin complexes, SMC complexes and transcription elongation complexes. These chapters will bring experts in the field up to date on several aspects of chromosome biology and will provide an exiting introduction to the field for new chromatin researchers. |
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Can variants in the constitutive heterochromatin of human chromosomes be detected consistently? by Michelle F Browner (Author) | |
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Polytene chromosomes, heterochromatin, and position effect variegation (Advances in genetics) by I. F Zhimulëv (Author) |
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