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Category: genetics – Page 388

Induction of anti-aging gene klotho with a small chemical compound that demethylates CpG islands

Klotho (KL) is described as an anti-aging gene because mutation of Kl gene leads to multiple pre-mature aging phenotypes and shortens lifespan in mice. Growing evidence suggests that an increase in KL expression may be beneficial for age-related diseases such as arteriosclerosis and diabetes. It remains largely unknown, however, how Kl expression could be induced. Here we discovered novel molecular mechanism for induction of Kl expression with a small molecule ‘Compound H’, N-(2-chlorophenyl)-1 H-indole-3-caboxamide. Compound H was originally identified through a high-throughput screening of small molecules for identifying Kl inducers. However, how Compound H induces Kl expression has never been investigated. We found that Compound H increased Kl expression via demethylation in CpG islands of the Kl gene. The demethylation was accomplished by activating demethylases rather than inhibiting methylases. Due to demethylation, Compound H enhanced binding of transcription factors, Pax4 and Kid3, to the promoter of the Kl gene. Pax4 and Kid3 regulated Kl promoter activity positively and negatively, respectively. Thus, our results show that demethylation is an important molecular mechanism that mediates Compound H-induced Kl expression. Further investigation is warranted to determine whether Compound H demethylates the Kl gene in vivo and whether it can serve as a therapeutic agent for repressing or delaying the onset of age-related diseases.

Keywords: klotho, methylation, Pax4, Kid3, CpG island.

Pre-mature aging phenotypes were eminent in the klotho (Kl)-deficient mice, which have ~ 10 copies of a transgene integrated in the 5’ flanking region of the Kl gene disrupting its expression [1]. The klotho mice die around ~ 2 months of age after birth due to multiple aging-related organ failures [1]. Later, the role of KL in aging was confirmed by the reproduction of the same aging phenotypes in Kl knockout homozygous (Kl −/−) mice [2]. On the other hand, overexpression of KL extends lifespan by 20–30% [2, 3]. The protein products of Kl gene can be divided into two forms: membrane-integrated form of Kl and non-integrated form of Kl which includes secreted and soluble Kl (sKl). These two type of proteins are produced from the two transcripts that arise from a single kl gene due to alternative RNA splicing [4, 5].

How resident microbes restructure body chemistry

The team compared germ-free (sterile) mice and mice with normal microbes. They used a laboratory technique called mass spectrometry to characterize the non-living molecules in every mouse organ. They identified as many molecules as possible by comparing them to reference structures in the GNPS database, a crowdsourced mass spectrometry repository developed by Dorrestein and collaborators. They also determined which living microbes co-locate with these molecules by sequencing a specific genetic region that acts as a barcode for bacterial types.

In total, they analyzed 768 samples from 96 sites of 29 different organs from four germ-free mice and four mice with normal microbes. The result was a map of all of the molecules found throughout the body of a normal mouse with microbes, and a map of molecules throughout a mouse without microbes.

A comparison of the maps revealed that as much as 70 percent of a mouse’s gut chemistry is determined by its gut microbiome. Even in distant organs, such as the uterus or the brain, approximately 20 percent of molecules were different in the mice with gut microbes.

Hacking DNA: The Story of CRISPR, Ken Thompson, and the Gene Drive

The very nature of the human race is about to change. This change will be radical and rapid beyond anything in our species’ history. A chapter of our story just ended and the next chapter has begun.

This revolution in what it means to be human will be enabled by a new genetic technology that goes by the innocuous sounding name CRISPR, pronounced “crisper”. Many readers will already have seen this term in the news, and can expect much more of it in the mainstream media soon. CRISPR is an acronym for Clustered Regularly Interspaced Short Palindromic Repeats and is to genomics what vi (Unix’s visual text editor) is to software. It is an editing technology which gives unprecedented power to genetic engineers: it turns them into genetic hackers. Before CRISPR, genetic engineering was slow, expensive, and inaccurate. With CRISPR, genome editing is cheap, accurate, and repeatable.

This essay is a very non-technical version of the CRISPR story concluding with a discussion of Gene Drive[1], a biological technique which, when used with CRISPR, gives even greater power to genetic engineers. The technical details go very deep and for those who are interested in diving in, I’ve included a number of useful pointers. At the end, I will very briefly discuss the implications of these two new technologies.

How to Battle an Epidemic? Digitize Its DNA and Share It With the World

Ogba Educational Clinic

A nightmarish scene was burnt into my memory nearly two decades ago: Changainjie, Beijing’s normally chaotic “fifth avenue,” desolate without a sign of life. Schools shut, subways empty, people terrified to leave their homes. Every night the state TV channels reported new cases and new deaths. All the while, we had to face a chilling truth: the coronavirus, SARS, was so novel that no one understood how it spread or how to effectively treat it. No vaccines were in sight. In the end, it killed nearly 1,000 people.

It’s impossible not to draw parallels between SARS and the new coronavirus outbreak, COVID-19, that’s been ravaging China and spreading globally. Yet the response to the two epidemics also starkly highlights how far biotech and global collaborations have evolved in the past two decades. Advances in genetic sequencing technologies, synthetic biology, and open science are reshaping how we deal with potential global pandemics. In a way, the two epidemics hold up a mirror to science itself, reflecting both technological progress and a shift in ethos towards collaboration.

Let me be clear: any response to a new infectious disease is a murky mix of science, politics, racism, misinformation, and national egos. It’s naïve to point to better viral control and say it’s because of technology alone. Nevertheless, a comparison of the two outbreaks dramatically highlights how the scientific world has changed, for the better, in the last two decades.

Gene-editing is more error-prone than thought, new findings suggest

The standard gene-editing tool, CRISPR-Cas9, frequently produces a type of DNA mutation that ordinary genetic analysis misses, claims new research published in the journal Proceedings of the National Academy of Sciences (PNAS). In describing these findings the researchers called such oversights “serious pitfalls” of gene editing (Skryabin et al., 2020). In all, the new results suggest that gene-editing is more error-prone than thought and, further, that identifying and discarding defective and unwanted outcomes is not as easy as generally supposed.

Gene-editing is more error-prone than thought, new findings suggest

CRISPR Enzyme on DNA (Photo: MIT News)

Dr. David Sinclair on aging and age reversal (compilation II on D. Sinclair by A. Grases)

Excerpts from Dr. David Sinclair appearances during 2019 and early 2020. The focus I highlight in this compilation is around the research in progress on aging, age-related diseases and biological age reversal.

Dr. Sinclair is a well-known geneticist, researcher and professor, first at MIT and since more than two decades ago, at Harvard University.

Links of original sources:

Joe Rogan Experience (Sep 2019): https://youtu.be/ZGLL77wYxe8

Rhonda Patrick interview (Nov 2019): https://youtu.be/5DtWqzalEnc

EdMylett interview (Dec 2019): https://youtu.be/-wApz_zqQIQ

Continue reading “Dr. David Sinclair on aging and age reversal (compilation II on D. Sinclair by A. Grases)” | >

Genetically Modified Bacteria Could Save The Bees

That bees are downright awesome is not up for debate. After all, they pollinate about a third of all the crops that we consume and help to support ecosystems worldwide. Yet the bees are in trouble, with a phenomenon known as colony collapse disorder (CCD) causing an alarming drop in numbers. Fortunately, a solution may be on the horizon in the form of genetically modified bacteria.

One thing that is a topic of great debate is the cause of CCD. Some studies point the finger at a particular class of pesticides called neonicotinoids, although many within the scientific community agree that multiple factors are probably at play.

What we do know is that CCD first became an issue once the Varroa mite became widespread, largely thanks to a global trade in European honeybees that brought them into contact with Asian parasites. At first, it was assumed that the mites were simply killing bees by sucking on their blood, although it later transpired that they also carried the lethal deformed wing virus (DWV), transmitting it into the bloodstream of the bees they feasted on.

The genetic secret of night vision

One of the most remarkable characteristics of the vertebrate eye is its retina. Surprisingly, the sensitive portions of the photoreceptor cells are found on the hind side of the retina, meaning that light needs to travel through living neural tissue before it can be detected. While the origin of the high optical quality of the retina remain largely uninvestigated, it has long been proposed that a peculiar DNA organization would serve to improve vision in nocturnal mammals. Researchers at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden now showed that the optical quality of the mouse retina increases in the first month after birth that imparts improved visual sensitivity under low light conditions. This improvement is caused by a compact organization of the genetic material in the cell nucleus of rod photoreceptor cells that responsible for dim light vision.

Our retina is an amazing feature of the eye of vertebrates. This -sensitive layer of is lining the back of the eye-ball and acts as a screen for images projected by the lens. The retina has a thickness of 130 to 500 micrometer and is composed of five layers of dense . Since the sensitive portions of the photoreceptor cells are found on the hind side of the retina, light needs to travel through this dense neural tissue to reach the photoreceptors. Researchers suggested that a certain compact arrangement of DNA in the cell nucleus of the rod photoreceptors could improve night vision in nocturnal animals but it remained unclear if and how would benefit from this organization of genetic material.

Scientists around the research group leader Moritz Kreysing at the Max Planck Institute of Molecular Cell Biology and Genetics together with colleagues from the TU Dresden and the Biozentrum at the Ludwig Maximilians Universität in Munich wanted to find out, if and why cells of retinal neural cells are optically special and what the implications for the transparency of the retina are. Transparency in this context means that each rod cell scatters less light, which causes it to be more transparent.

CRISPR handbook – Free PDF download

The CRISPR Handbook – Enabling Genome Editing and Transforming Life Science Research is GenScript’s comprehensive guide to the CRISPR/Cas9 genome editing revolution. This new resource includes:

An introductory history of genome editing. The current applications for CRISPR/Cas9 in genome editing. An updated overview of expanded CRISPR research applications, including immunoprecipitation, epigenetic modification, live imaging, and therapeutics. New CRISPR/Cas9 workflows and case studies to help you start using this technology in your research.

CRISPR Handbook – Enabling Genome Editing and Transforming Life Science Research. Free PDF download on the CRISPR/Cas9 genome editing revolution, including CRISPR KO & KI workflows, case studies, and references.

Oldest reconstructed bacterial genomes link farming, herding with emergence of new disease

The Neolithic revolution, and the corresponding transition to agricultural and pastoralist lifestyles, represents one of the greatest cultural shifts in human history, and it has long been hypothesized that this might have also provided the opportunity for the emergence of human-adapted diseases. A new study published in Nature Ecology & Evolution led by Felix M. Key, Alexander Herbig, and Johannes Krause of the Max Planck Institute for the Science of Human History studied human remains excavated across Western Eurasia and reconstructed eight ancient Salmonella enterica genomes—all part of a related group within the much larger diversity of modern S. enterica. These results illuminate what was likely a serious health concern in the past and reveal how this bacterial pathogen evolved over a period of 6,500 years.

Searching for ancient pathogens

Most do not cause any lasting impact on the skeleton, which can make identifying affected archaeological remains difficult for scientists. In order to identify past diseases and reconstruct their histories, researchers have turned to genetic techniques. Using a newly developed bacterial screening pipeline called HOPS, Key and colleagues were able to overcome many of the challenges of finding ancient pathogens in metagenomics data.