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Category: genetics – Page 486

You are the company you keep—A new screening method detects direct biomolecule interactions

Proteins are the building blocks of the cell. They do most of the work and are essential for the structure, function and dynamic regulation of the cell and body’s tissues and organs. Proteins rarely work alone, they interact, form protein complexes or bind DNA and RNA to control what a cell does. These complexes are key pieces of many important reactions within the cell, such as energy metabolism or gene regulation. Any change in those interactions, which can for example be caused by a mutation, can make the difference between health and disease. Hence, for understanding how cells operate, or what might go wrong in ill cells, it is essential to know how their building blocks interact.

New technologies allowed scientists during the last decades to understand the genetic information an organism possess, which of this information is actively used and which proteins are made by the cell in different circumstances. Now it is a big challenge to understand how biomolecules such as proteins and RNA messenger molecules combine to form the complexes required for a functional cell. In other words, we know the ten thousands of parts a cell is build off, but we don’t know how they belong together.

In a paper published in Nature Communications, scientists at the Centre for Genomic Regulation (CRG) describe the development of a new method, named “rec-YnH”, which was designed to understand the complexes formed between hundreds of proteins and RNAs at the same time.

DNA ‘dances’ in first explanation of how genetic material flows through a nucleus

“Previous work mostly focused on what was going on at the microscale of DNA,” says study co-author Michael Shelley, group leader for biophysical modeling at the Flatiron Institute’s Center for Computational Biology in New York City and co-director of the Courant Institute’s Applied Mathematics Laboratory at New York University. “People didn’t really think about what was going on at the larger scale.”

Shelley and colleagues simulated the motions of chromatin, the functional form of DNA inside the nucleus. Chromatin looks like beads on a string, with ball-like clusters of genetic material linked by strands of DNA. The researchers propose that molecular machines along the DNA cause segments of the chromatin to straighten and pull taut. This activity aligns neighboring strands to face the same direction. That alignment, in turn, results in a cascading waltz of genetic material shimmying across the nucleus.

The dancing DNA may play a role in gene expression, replication and remodeling, though the exact effects remain unclear, the researchers reported online October 22 in Proceedings of the National Academy of Sciences.

Regenerage — Spinal Cord Regeneration — Venga la Alegria — TV Azteca — Bioquark Inc.

Wonderful to see the continuing progress of Mr. Omar Flores, with the support of his lovely wife, actress Mayra Sierra, today on the Venga la Alegria (VLA) show on TV Azteca (http://www.aztecauno.com/vengalaalegria) — The importance of an integrated approach to curing spinal cord injury including family, physical therapists, and the medical team at Regenerage (https://regenerage.clinic/)

Dr. David Sinclair AMA

On the 23rd of this month, Dr. David Sinclair did an Ask Me Anything over at the Futurology subreddit in support of the NAD+ Mouse Project on Lifespan.io. There were a range of interesting questions from the community about his work in aging research, particularly the role of NAD+ in aging.

Dr. David A. Sinclair is a Professor in the Department of Genetics at Harvard Medical School and a co-joint Professor in the Department of Physiology and Pharmacology at the University of New South Wales. He is the co-Director of the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging and a Senior Scholar of the Ellison Medical Foundation. He obtained his Ph.D. in Molecular Genetics at the University of New South Wales, Sydney in 1995. He worked as a postdoctoral researcher at M.I.T. with Dr. Leonard Guarente; there, he co-discovered a cause of aging for yeast as well as the role of Sir2 in epigenetic changes driven by genome instability.

More recently, he has been in the spotlight for his work with NAD+ precursors and their role in aging and has been helping to develop therapies that replace NAD+, which is lost with aging, in order to delay the diseases of old age. Below are a selection of questions and answers from the AMA, and we urge you to head over to Reddit Futurology to check out the other questions that people asked.

Mutations Accumulate in Healthy Esophageal Tissue With Age

Many mutations accumulate in the esophagus as we age.

Scientists at the MRC Cancer Unit of the Wellcome Sanger Institute and other departments of the University of Cambridge discovered that healthy esophageal tissue accumulates very high numbers of mutations with age, to the point that, by the time middle age is reached, it is likely to contain more cells with a particular mutation than cells without it [1].

Abstract

The extent to which cells in normal tissues accumulate mutations throughout life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant clones in normal esophageal epithelium from nine donors (age range, 20 to 75 years). Somatic mutations accumulated with age and were caused mainly by intrinsic mutational processes. We found strong positive selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of clones per square centimeter. In middle-aged and elderly donors, clones with cancer-associated mutations covered much of the epithelium, with NOTCH1 and TP53 mutations affecting 12 to 80% and 2 to 37% of cells, respectively. Unexpectedly, the prevalence of NOTCH1 mutations in normal esophagus was several times higher than in esophageal cancers. These findings have implications for our understanding of cancer and aging.

Protein Produced by Astrocytes Involved in Brain Plasticity

Protein Chrdl1 appears to regulate brain plasticity.

Researchers from the Salk Institute have discovered that a protein called Chrdl1, secreted by astrocytes, is responsible for driving synapse maturation and limiting brain plasticity later in life [1].

Abstract

In the developing brain, immature synapses contain calcium-permeable AMPA glutamate receptors (AMPARs) that are subsequently replaced with GluA2-containing calcium-impermeable AMPARs as synapses stabilize and mature. Here, we show that this essential switch in AMPARs and neuronal synapse maturation is regulated by astrocytes. Using biochemical fractionation of astrocyte-secreted proteins and mass spectrometry, we identified that astrocyte-secreted chordin-like 1 (Chrdl1) is necessary and sufficient to induce mature GluA2-containing synapses to form. This function of Chrdl1 is independent of its role as an antagonist of bone morphogenetic proteins (BMPs). Chrdl1 expression is restricted to cortical astrocytes in vivo, peaking at the time of the AMPAR switch. Chrdl1 knockout (KO) mice display reduced synaptic GluA2 AMPARs, altered kinetics of synaptic events, and enhanced remodeling in an in vivo plasticity assay.

Dr. Sam Palmer – Thymic Involution and Cancer Risk

Cancer is the poster child of age-related diseases, and a recent study sheds light on why the risk of cancer rises dramatically as we age.

Abstract

For many cancer types, incidence rises rapidly with age as an apparent power law, supporting the idea that cancer is caused by a gradual accumulation of genetic mutations. Similarly, the incidence of many infectious diseases strongly increases with age. Here, combining data from immunology and epidemiology, we show that many of these dramatic age-related increases in incidence can be modeled based on immune system decline, rather than mutation accumulation. In humans, the thymus atrophies from infancy, resulting in an exponential decline in T cell production with a half-life of ∼16 years, which we use as the basis for a minimal mathematical model of disease incidence. Our model outperforms the power law model with the same number of fitting parameters in describing cancer incidence data across a wide spectrum of different cancers, and provides excellent fits to infectious disease data.

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