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Category: genetics – Page 283

Aberrant activation of Wnt/β-catenin pathway is a key driver of colorectal cancer (CRC) growth and of great therapeutic importance. In this study, we performed comprehensive CRISPR screens to interrogate the regulatory network of Wnt/β-catenin signaling in CRC cells. We found marked discrepancies between the artificial TOP reporter activity and β-catenin–mediated endogenous transcription and redundant roles of T cell factor/lymphoid enhancer factor transcription factors in transducing β-catenin signaling. Compiled functional genomic screens and network analysis revealed unique epigenetic regulators of β-catenin transcriptional output, including the histone lysine methyltransferase 2A oncoprotein (KMT2A/Mll1). Using an integrative epigenomic and transcriptional profiling approach, we show that KMT2A loss diminishes the binding of β-catenin to consensus DNA motifs and the transcription of β-catenin targets in CRC. These results suggest that KMT2A may be a promising target for CRCs and highlight the broader potential for exploiting epigenetic modulation as a therapeutic strategy for β-catenin–driven malignancies.

Colorectal cancer (CRC) represents one of the major malignancies and a leading cause of cancer-related death worldwide. Aberrant Wnt/β-catenin pathway plays a pivotal role in colon carcinogenesis (1). Cytoplasmic β-catenin is phosphorylated by a protein complex containing adenomatous polyposis coli (APC), AXIN1 or AXIN2, casein kinase 1α (CK1α), and glycogen synthase kinase-3β (GSK3β), leading to β-catenin destruction through ubiquitin-proteasome system. Wnt binding to the LDL receptor related protein 5/6 (LRP5/6)–frizzled receptors results in the disassembly of the β-catenin–destruction complex and consequent accumulation of β-catenin. β-Catenin then enters into the nucleus and binds to T cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors to initiate the transcription of β-catenin downstream targets (2).

Nearly all colorectal tumors (CRC) harbor genetic mutations that lead to the hyperactivation of β-catenin signaling. For example, germline or spontaneous mutations in tumor suppressor APC may cause constitutive activation of β-catenin in colon stem cells and the development of colonic polyps, which may eventually evolve into colorectal carcinomas. Hyperactivated β-catenin initiates the expression of various downstream targets through binding to the promoter regions via TCF/LEF transcription factors. Studies using transcriptomic approaches have characterized various β-catenin–responsive targets, such as cMYC, AXIN2, ASCL2, LGR5, and CD44. Collectively, these targets promote proliferation (e.g., cMYC) and maintain a stem cell state (e.g., LGR5 and ASCL2), highlighting the potential value of developing treatments that target β-catenin signaling in cancer. However, β-catenin itself is an intractable drug target (6, 7).

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Mutations in the RAB39B gene cause X-linked intellectual disability (XLID), comorbid with autism spectrum disorders or early Parkinson’s disease. One of the functions of the neuronal small GTPase RAB39B is to drive GluA2/GluA3 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) maturation and trafficking, determining AMPAR subunit composition at glutamatergic postsynaptic neuronal terminals. Taking advantage of the Rab39b knockout murine model, we show that a lack of RAB39B affects neuronal dendritic spine refinement, prompting a more Ca2+-permeable and excitable synaptic network, which correlates with an immature spine arrangement and behavioural and cognitive alterations in adult mice. The persistence of immature circuits is triggered by increased hypermobility of the spine, which is restored by the Ca2+-permeable AMPAR antagonist NASPM.

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A team of researchers from Verve Therapeutics and the Perelman School of Medicine at the University of Pennsylvania has developed a CRISPR gene-editing technique that lowered the levels of cholesterol in the blood of test monkeys. In their paper published in the journal Nature, the researchers describe their technique.

Prior research has shown that in some people, the PCSK9 gene codes excess PCSK9 protein production (which occurs mostly in the liver)—leading to an increase in lipoprotein cholesterol levels in the bloodstream. This is because it interferes with blood cells with LDL receptors that “grab” LDL and remove it. For this reason, have developed therapies that reduce the production of PCSK9 protein. However, most do not work well enough, which is why there is still so much atherosclerotic cardiovascular disease. In this new effort, the researchers have tried another approach—altering the PCSK9 gene to make it stop coding for PCSK9 protein production.

The approach involved using a base editing technology made up of messenger RNA encoding for an along with guided RNA that was packaged in a lipid nanoparticle. Notably, the base editing technique was able to substitute a single nucleotide with another in the DNA without cutting the double helix. Prior research has shown the technique to be more precise, which means fewer errors than other CRISPR techniques. In their work, the researchers replaced an adenine with a guanine and a thymine with a cytosine, completely incapacitating the gene. Implementation of the therapy involved a one-time injection into the liver of cynomolgus monkeys.

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Origin of Information —“Something Very Old, Very Powerful and Very Special has Been Unleashed on Earth” | The Daily Galaxy.

“Humans are strange…We are the aliens,” observes Columbia University astrophysicist, Caleb Scharf, noting that humans are a striking anomaly in the natural world. “We also have a truly outsize impact on the planetary environment without much in the way of natural attrition to trim our influence (at least not yet).

Like a Sudden Invasion by Extraterrestrials

Continue reading “Origin of Information –“Something Very Old, Very Powerful and Very Special has Been Unleashed on Earth”” | >

Wines and table grapes exist thanks to a genetic exchange so rare that it’s only happened twice in nature in the last 6 million years. And since the domestication of the grapevine 8000 years ago, breeding has continued to be a gamble.

When today’s growers cultivate new varieties – trying to produce better-tasting and more disease-resistant grapes – it takes two to four years for breeders to learn whether they have the genetic ingredients for the perfect flower.

Females set fruit, but produce sterile pollen. Males have stamens for pollen, but lack fruit. The perfect flower, however, carries both sex genes and can self-pollinate. These hermaphroditic varieties generally yield bigger and better-tasting berry clusters, and they’re the ones researchers use for additional cross-breeding.

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DNA was personified in Jurassic Park, where the animated double helix that called himself Mr. DNA took you and a group of skeptical scientists through the oversimplified (and obviously fictional) steps to creating dino DNA — but there is some reality in this.

For all you dinosaur enthusiasts out there, synthesizing DNA can’t bring T.Rex and Brachiosaurus back from extinction. Though creating genes in a lab sounds like the original eureka moment of Jurassic Park, synthesizing human DNA has done everything from genetic sequencing and editing to detecting diseases like the current plague we are living through. There is just one step that has always been problematic.

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To answer this question, an internal team of scientists, consisting of researchers affiliated with the Buck Institute for Research on Ageing, and researchers from Nanjing University decided to modify both the Insulin and the rapamycin pathways of a group of C.elegans worms, expecting to see a cumulative result of a 130% increase in lifespan. However, instead of seeing a cumulative effect in lifespan, the worms lived five times longer than they normally would.

“The synergistic extension is really wild. The effect isn’t one plus one equals two, it’s one plus one equals five. Our findings demonstrate that nothing in nature exists in a vacuum; in order to develop the most effective anti-aging treatments we have to look at longevity networks rather than individual pathways.” – Jarad Rollins of Nanjing University.

What could this mean for human regenerative medicine? Humans are not worms, however on a cellular level they do possess very similar biology. Both the insulin pathway and the rapamycin pathway are what is known as ‘conserved’ between humans and C.elegans, meaning that these pathways have been maintained in both organisms. In the distant past, both humans and C.elegans had a common ancestor, in exactly the same way as humans and Chimpanzees have a common ancestor. Evolution has changed our bodies significantly over the millions of years that humans and C.elegans have diverged from one another, but a lot of our fundamental biological functions remain largely unchanged.

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Most important part comes at 1:49 where Liza talks about gene therapies for people to stop people from aging, reaching homeostasis, or even exceeding it a little bit.

In this video Liz introduces BioViva Science and how the company works with its partners in delivering gene therapies.

Liz Parrish is the Founder and CEO of BioViva Sciences USA Inc. BioViva is committed to extending healthy lifespans using gene therapy. Liz is known as “the woman who wants to genetically engineer you,” she is a humanitarian, entrepreneur, author and innovator and a leading voice for genetic cures. As a strong proponent of progress and education for the advancement of gene therapy, she serves as a motivational speaker to the public at large for BioViva and the life sciences. She is actively involved in international educational media outreach and is a founding member of the International Longevity Alliance (ILA). She is the founder of the BioTrove Podcasts, found at iTunes, which is committed to offering a meaningful way for people to learn about current technologies. She is also a founding member of the American Longevity Alliance (ALA) a 501©(3) nonprofit trade association that brings together individuals, companies, and organizations who work in advancing the emerging field of cellular & regenerative medicine with the aim to get governments to consider aging a disease.

Continue reading “Fighting Aging With Gene Therapies | Liz Parrish Interview Series Episode 2” | >