Daily Archives: October 7, 2020

In 1986, geneticist Thomas Roderick, Ph.D., sat with about 10 colleagues in a bar in Bethesda, Maryland, discussing all-things biology. After a few rounds of drinks, Roderickis said to havethrown out a new term for the study and comparison of genomes across species: "genomics." The term then appeared in scientific literature for the first time a year later.

Genomics now a household word was greatly elevated in stature in October 1990 with the worldwide launch of the Human Genome Project. This month marks the 30th anniversary of the endeavor, biology's audacious odyssey that deciphered the first sequence of the 3 billion DNA letters making up the human genetic blueprint the human genome.

The project showed that humans have 99.9% identical genomes, and it set the stage for developing a catalog of human genes and beginning to understand the complex choreography involved in gene expression. The growing knowledge about the structure and function of the human genome is now regularly used in biotechnology and medicine.

"The Human Genome Project transformed the way we study our biology and medicine. From accessing a genome sequence at the click of a mouse, performing newborn genome sequencing in an intensive care unit or the group's revolutionary decision to share the data with all, the Project's intentions and goals have spilled into how we do science today," said Francis Collins, M.D., Ph.D., National Institutes of Health director.

From accessing a genome sequence at the click of a mouse, performing newborn genome sequencing in an intensive care unit or the group's revolutionary decision to share the data with all, the Project's intentions and goals have spilled into how we do science today.

Thirty years after this historic launch, the field of genomics continues to expand significantly, building upon the Human Genome Project's successes.

Generating the first human genome sequence required actively sequencing human DNA for 6-8 years; today, scientists can sequence a human genome in a day. Such fast human genome sequencing allows physicians to make quick diagnoses of rare genetic disorders in acute settings.

Another notable achievement since the end of the Human Genome Project is the reduced cost of sequencing a human genome. That price has dropped from a billion dollars to mere hundreds, thanks to federal investments used to develop new technologies for DNA sequencing.

"This 30-year milestone is not only an opportunity to reflect on past accomplishments, but a time to look ahead," said Eric Green, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI). "Over the last 30 years, NHGRI has regularly partnered with the research community to create strategic visions for each phase of human genomics. To commemorate the Human Genome Project's launch 30 years ago, we chose this month to publish NHGRI's new vision for human genomics, a product of the last two-plus years of strategic planning.

To commemorate the Human Genome Project's launch 30 years ago, we chose this month to publish NHGRI's new vision for human genomics, a product of the last two-plus years of strategic planning.

NHGRI has published two strategic visions since the end of the Human Genome Project, in2003and2011. NHGRI will unveil its 2020 Strategic Vision in late October.

Visit genome.gov/2020SVto learn more.

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The Human Genome Project turns the big 3-0! - National Human Genome Research Institute

When the brain forms a memory of a new experience, neurons called engram cells encode the details of the memory and are later reactivated whenever we recall it. A new MIT study reveals that this process is controlled by large-scale remodeling of cells' chromatin.

This remodeling, which allows specific genes involved in storing memories to become more active, takes place in multiple stages spread out over several days. Changes to the density and arrangement of chromatin, a highly compressed structure consisting of DNA and proteins called histones, can control how active specific genes are within a given cell.

"This paper is the first to really reveal this very mysterious process of how different waves of genes become activated, and what is the epigenetic mechanism underlying these different waves of gene expression," says Li-Huei Tsai, the director of MIT's Picower Institute for Learning and Memory and the senior author of the study.

Asaf Marco, an MIT postdoc, is the lead author of the paper, which appears today in Nature Neuroscience.

Epigenomic controlEngram cells are found in the hippocampus as well as other parts of the brain. Many recent studies have shown that these cells form networks that are associated with particular memories, and these networks are activated when that memory is recalled. However, the molecular mechanisms underlying the encoding and retrieval of these memories are not well-understood.

Neuroscientists know that in the very first stage of memory formation, genes known as immediate early genes are turned on in engram cells, but these genes soon return to normal activity levels. The MIT team wanted to explore what happens later in the process to coordinate the long-term storage of memories.

"The formation and preservation of memory is a very delicate and coordinated event that spreads over hours and days, and might be even months -- we don't know for sure," Marco says. "During this process, there are a few waves of gene expression and protein synthesis that make the connections between the neurons stronger and faster."

Tsai and Marco hypothesized that these waves could be controlled by epigenomic modifications, which are chemical alterations of chromatin that control whether a particular gene is accessible or not. Previous studies from Tsai's lab have shown that when enzymes that make chromatin inaccessible are too active, they can interfere with the ability to form new memories.

To study epigenomic changes that occur in individual engram cells over time, the researchers used genetically engineered mice in which they can permanently tag engram cells in the hippocampus with a fluorescent protein when a memory is formed. These mice received a mild foot shock that they learned to associate with the cage in which they received the shock. When this memory forms, the hippocampal cells encoding the memory begin to produce a yellow fluorescent protein marker.

"Then we can track those neurons forever, and we can sort them out and ask what happens to them one hour after the foot shock, what happens five days after, and what happens when those neurons get reactivated during memory recall," Marco says.

At the very first stage, right after a memory is formed, the researchers found that many regions of DNA undergo chromatin modifications. In these regions, the chromatin becomes looser, allowing the DNA to become more accessible. To the researchers' surprise, nearly all of these regions were in stretches of DNA where no genes are found. These regions contain noncoding sequences called enhancers, which interact with genes to help turn them on. The researchers also found that in this early stage, the chromatin modifications did not have any effect on gene expression.

The researchers then analyzed engram cells five days after memory formation. They found that as memories were consolidated, or strengthened, over those five days, the 3D structure of the chromatin surrounding the enhancers changed, bringing the enhancers closer to their target genes. This still doesn't turn on those genes, but it primes them to be expressed when the memory is recalled.

Next, the researchers placed some of the mice back into the chamber where they received the foot shock, reactivating the fearful memory. In engram cells from those mice, the researchers found that the primed enhancers interacted frequently with their target genes, leading to a surge in the expression of those genes.

Many of the genes turned on during memory recall are involved in promoting protein synthesis at the synapses, helping neurons strengthen their connections with other neurons. The researchers also found that the neurons' dendrites -- branched extensions that receive input from other neurons -- developed more spines, offering further evidence that their connections were further strengthened.

Primed for expression

The study is the first to show that memory formation is driven by epigenomically priming enhancers to stimulate gene expression when a memory is recalled, Marco says.

"This is the first work that shows on the molecular level how the epigenome can be primed to gain accessibility. First, you make the enhancers more accessible, but the accessibility on its own is not sufficient. You need those regions to physically interact with the genes, which is the second phase," he says. "We are now realizing that the 3D genome architecture plays a very significant role in orchestrating gene expression."

The researchers did not explore how long these epigenomic modifications last, but Marco says he believes they may remain for weeks or even months. He now hopes to study how the chromatin of engram cells is affected by Alzheimer's disease. Previous work from Tsai's lab has shown that treating a mouse model of Alzheimer's with an HDAC inhibitor, a drug that helps to reopen inaccessible chromatin, can help to restore lost memories.

Reference: Marco A, Meharena HS, Dileep V, et al.Mapping the epigenomic and transcriptomic interplay during memory formation and recall in the hippocampal engram ensemble. Nat. Neurosci. 2020. doi:10.1038/s41593-020-00717-0

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Genomic Remodeling Revealed To Control How We Make Memories - Technology Networks

Genomic analysis using circulating cell-free tumor DNA (ctDNA) was highly concordant with, and complementary to, tissue genomic analysis among patients with advanced renal cell carcinoma (mRCC), according to results of a retrospective study presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.

Exclusive GAs [genomic alterations] found on both platforms suggests tumor evolution over time and treatment, which may assist in guiding treatment selection in mRCC, Zeynep Zengin, MD, of City of Hope Comprehensive Cancer Center in Duarte, California, and presenter of the study, said.

The single-center, retrospective studied analyzed data from 847consecutive patients with stage IIIB to IV RCC who underwent ctDNA testing using the Guardant360 next-generation sequencing (NGS) assay. Serial assessment of ctDNA was performed on a subset of 39 patients. GAs detected by ctDNA NGS were compared with GAs detected by NGS or whole-exome sequencing of tissue DNA with commercially available platforms (Foundation Medicine and Ashion Analytics, respectively). The median time between the ctDNA and tissue testing was 15.3 months.

Among the ctDNA samples, 72% harbored 1 or more GA, with the most frequent genes affected including TP53 at 37%, VHL at 22%, and EGFR at 6%.

Alterations along the mTOR pathway were also well represented, including PTEN, PIK3CA, and NF1, Dr Zengin said. She noted that approximately 6% of patients harbored mutations in DNA repair genes, such as BRCA1, BRCA2, ATM, and CDK12.

Serial analysis of ctDNA demonstrated that the frequency of GAs in EGFR and PTEN increased over time.

Among the tissue DNA samples, the most frequent genes with GAs was VHL at 63.8%, PMBRM1 at 44.7%, and SETD2 at 39.1%. Both PMBRM1 and SETD2 were not evaluated by the ctDNA assay.

A total of 154 GAs were detected across both ctDNA and tissue DNA assay, when including only the genes assessed by the ctDNA assay. Of these GAs, 17.4% were identified by both tests, whereas 38.8% were detected only in blood and 43.8% were detected only in tissue.

The overlap increased when samples were stratified by the amount of time between their collections. When samples were collected within 6 months of each other, the overlap was 39.3%, whereas samples collected more than 6 months apart had an overlap of 10.8%.

The concordance was high between the tests, with a cumulative rate of 96.2%.

Dr Zengin concluded that concordance analysis suggests that ctDNA and tissue-based genomic profiling are complementary.

Disclosures: Multiple authors declared affiliations with industry. Please refer to the original abstract for a full list of disclosures.

Read more of Cancer Therapy Advisors coverage of the ESMO Virtual Congress 2020 by visiting the conference page.

Reference

Zengin ZB, Weipert C, Hsu J, et al. Assessment of circulating cell-free tumor DNA (ctDNA) in 847 patients (pts) with metastatic renal cell carcinoma (mRCC) and concordance with tissue-based testing. Presented at: European Society for Medical Oncology (ESMO) Virtual Congress 2020; September 19-21, 2020. Abstract 701O.

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ctDNA Concordant with Tissue Genomic Analysis in RCC - Cancer Therapy Advisor

Alexander Heinl Image: American biochemist Jennifer A. Doudna, left, and the French microbiologist Emmanuelle Charpentier, right, Frankfurt, Germany.

LONDON Two women were awarded the Nobel Prize in chemistry Wednesday for their pioneering work on genome editing, which has the life-saving potential to be used to cure genetic diseases.

"This year's prize is about re-writing the code of life," said Secretary General Gran K. Hansson for the Royal Swedish Academy of Sciences, as he awarded the prize to American biologist Jennifer Doudna and French microbiologist Emmanuelle Charpentier.

Only five women have previously won the chemistry prize, which has been awarded 111 times between 1901 and 2019 to 183 people.

Doudna and Charpentier developed a type of genetic scissor called the CRISPR/Cas9 used "to change the DNA of animals, plants and microorganisms with extremely high precision," according to the chemistry prize committee.

The "revolutionary" method has contributed to new cancer therapies and has the potential to be used in curing inheritable diseases.

"It has not only revolutionized basic science, but also resulted in innovative crops and will lead to ground-breaking new medical treatments," said Claes Gustafsson, chair of the chemistry committee, in a statement.

In addition to making major developments to genetic research, Charpentier told the news conference by phone that she hopes the prize encourages girls to pursue science.

"I wish that this will provide a positive message to show them in principle woman in science can also be awarded prizes but more importantly, women in science can also have an impact for the research they're performing," she said.

Last year's chemistry award went to American chemist John B. Goodenough, British American chemist M. Stanley Whittingham and Japanese chemist Akira Yoshino for their development of the long-life lithium-ion battery.

The prestigious prize was established by the Swedish inventor Alfred Nobel who dictated in his will that it would honor "those who, during the preceding year, have conferred the greatest benefit to humankind."

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Winners are given a Nobel diploma and medal, and share the prize money of 10 million Swedish kronor (more than $1.1 million).

The other prizes still to be delivered in the coming days are for outstanding work in the fields of literature, peace and economics.

The Associated Press contributed to this report.

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'Re-writing the code of life': Nobel chemistry prize goes to genome editing pioneers - msnNOW