Breaking News
March 25, 2019 - Benefits of osteoporosis treatment in postmenopausal women outweigh the perceived risks
March 25, 2019 - Researchers find evidence of Cryptosporidium parasite in Minnesota’s public water systems
March 25, 2019 - Three Clues to Raised Risk of Miscarriage
March 25, 2019 - Structured play helps toddlers self-regulate, altering their life course
March 25, 2019 - Translating horror into justice: Stanford psychiatrist advocates for human rights
March 25, 2019 - HORIBA Medical introduces D-Dimer reagent for Yumizen G hemostasis range
March 25, 2019 - Recurrent pregnancy loss may be caused by sperm DNA damage, finds study
March 25, 2019 - Special Collection tracks development of new diagnostic tests for tuberculosis
March 25, 2019 - Air Force develops genetic test to predict mental performance
March 25, 2019 - To abort or not to abort—making difficult choices alone
March 25, 2019 - Computer vision technology could aid ICU care by spotting movement
March 25, 2019 - IONTAS wins ‘Small Business of the Year’ category at Cambridge News Business Excellence Awards 2019
March 25, 2019 - First postpartum depression drug gets FDA nod
March 25, 2019 - Research Recognition Award will help improve lives of young people with absence epilepsy
March 25, 2019 - Bisphosphonates to treat osteoporosis appears to be beneficial for all women
March 25, 2019 - Dolomite Bio releases new Drop-seq datasets for single-cell RNA sequencing
March 25, 2019 - Hemoglobin A1c blood test may underestimate prevalence of diabetes
March 25, 2019 - Eating leafy green vegetables may help maintain muscle strength and mobility
March 25, 2019 - BMA secures state-backed clinical negligence indemnity scheme for GP trainees
March 25, 2019 - Biohaven Announces Completion of Pre-NDA Meeting With FDA for Oral CGRP Receptor Antagonist Rimegepant
March 25, 2019 - Adding breakfast to classrooms may have a health downside
March 25, 2019 - She Was Dancing On The Roof And Talking Gibberish. A Special Kind Of ER Helped Her.
March 25, 2019 - KNAUER introduces new Sepapure FPLC columns and media for protein purification tasks
March 25, 2019 - Weight loss in obese migraine sufferers can improve their quality of life
March 25, 2019 - Exposure to particulate air pollution may lead to reduced sperm production
March 25, 2019 - Synthetic peptide appears to disrupt inflammation and protect kidneys from nephritis
March 25, 2019 - New guideline focuses on strategies to improve health of older adults with diabetes
March 25, 2019 - Study evaluates prescribing of preventive drugs at the end of life in older adults with cancer
March 25, 2019 - Radial or femoral approaches for PCI are equal in terms of survival in heart attack patients
March 25, 2019 - Study shows how some autoimmune diseases are more closely related than others
March 25, 2019 - Long term opioid medications impacts production of important hormones
March 25, 2019 - FDA Issues Complete Response Letter for Zynquista (sotagliflozin)
March 25, 2019 - CDC researchers report on trends in hospital breastfeeding policies
March 25, 2019 - States Push For Caregiver Tax Credits
March 25, 2019 - Females on ketogenic diet fail to show metabolic benefits in animal model
March 25, 2019 - Modulating stiffness of blood-forming stem cells could facilitate mobilization procedures
March 25, 2019 - Gene editing regulations to be tightened
March 25, 2019 - CPAP treatment can result in weight loss in people with sleep apnea and obseity
March 25, 2019 - Highly attractive businesswomen are considered less trustworthy ‘femmes fatales’
March 25, 2019 - Breast Density Categorization Varies With Screening Modality
March 25, 2019 - Researchers explore link between metal exposure and Parkinson’s symptoms
March 25, 2019 - Later meal timing may contribute to weight gain
March 25, 2019 - Around one in hundred people has autism spectrum condition in China
March 25, 2019 - Research paves way for new standard of care to improve heart’s pump function
March 25, 2019 - Exposure to HIV virus, antiretroviral therapy before birth linked to obesity and asthma-like symptoms
March 25, 2019 - Transgender men preserve their fertility potential after one year of testosterone therapy
March 25, 2019 - Tighter Blood Pressure Control May Prevent Brain Lesions
March 25, 2019 - A reward now or later? Exploring impulsivity in Parkinson’s disease patients
March 25, 2019 - Financial incentives fail to increase completion rates of colorectal cancer screening tests mailed to patients
March 25, 2019 - New research program launched to highlight sexual harassment in academia
March 25, 2019 - Hemoglobin A1c blood test does not detect diabetes in most patients, shows study
March 25, 2019 - Wyss Technology licensed by Sherlock Biosciences to create affordable molecular diagnostics
March 25, 2019 - DWK Life Sciences launches KIMBLE GLS 80 Media Bottle and Multiport Cap System
March 25, 2019 - New study aims to reduce online sexual exploitation of children
March 25, 2019 - Want healthier eating habits? Start with a workout
March 25, 2019 - New approach to prescribing antibiotics could curb resistance
March 24, 2019 - Theravance Biopharma Announces First Patient Dosed in Phase 2b/3 Study of TD-1473 in Patients with Ulcerative Colitis
March 24, 2019 - Prenatal DHA prevents blood-pressure increase from obesity during childhood
March 24, 2019 - Combined immunosuppression may be effective, safe in treating older patients with Crohn’s disease
March 24, 2019 - GSK sells health drinks arm, buys US cancer treatment firm
March 24, 2019 - Bacteria and innate immune factors in birth canal, cervix may be key to predicting preterm births
March 24, 2019 - IgG antibodies play unexpected role in atherosclerosis
March 24, 2019 - Sounds and vibrations are quite similar for the brain, finds new study
March 24, 2019 - Practices for Reducing COPD Hospital Readmissions Explored
March 24, 2019 - Could an eye doctor diagnose Alzheimer’s before you have symptoms?
March 24, 2019 - Enzyme inhibitor stops inflammation and neurodevelopmental disorders in mouse models
March 24, 2019 - Walk, Dance, Clean: Even a Little Activity Helps You Live Longer
March 24, 2019 - Americans used less eye care in 2014 versus 2008
March 24, 2019 - Study finds link between depression in 20s linked to memory loss in 50s
March 24, 2019 - New tool helps physiotherapy students to master complex fine motor skills
March 24, 2019 - The AMR Centre secures £2.3m funding boost
March 24, 2019 - Study examines effects of taking ondansetron during first trimester of pregnancy
March 24, 2019 - Researchers identify a more effective treatment for cancer
March 24, 2019 - Open-source solution for multiparametric optical mapping of the heart’s electrical activity
March 24, 2019 - New nanotechnology approach shows promise in treating triple negative breast cancer
March 24, 2019 - Trevena Announces Publication of APOLLO-1 Results in The Journal of Pain Research Highlighting Oliceridine’s Potential for Management of Moderate-to-Severe Acute Pain
March 24, 2019 - Maternal deaths following C-section 50 times higher in Africa compared to high-income countries
March 24, 2019 - Apple watch could detect irregular heart beat says study
March 24, 2019 - Queen Mary University of London’s BCI boosts radionuclide imaging capabilities with MILabs VECTor technology
March 24, 2019 - Girls should be encouraged to gain more ball skills, shows study
‘DNA origami’ triggers tissue generation in early development | News Center

‘DNA origami’ triggers tissue generation in early development | News Center

image_pdfDownload PDFimage_print

A developing embryo faces the difficult task of concocting myriad tissue types — including skin, bone and the specialized glop that makes up our internal organs and immune system — from essentially the same set of ingredients: immature, seemingly directionless stem cells. Although some of the important players that provide direction to this transformation are known, it’s not been clear exactly how they work together to accomplish this feat.

Now, researchers at the Stanford University School of Medicine have identified a key regulatory hierarchy in which proteins called morphogens control gene expression by directing the looping of DNA in a cell. This looping brings master regulators called transcription factors in contact with specific sets of genes necessary to make particular tissue types. 

Varying concentrations and types of morphogens cause different looping events, directing different cell fates much in the same way that railroad workers control the direction and eventual destination of a train car by connecting different portions of track.  

Although the researchers were particularly interested in learning more about how to stimulate the production of a type of skin cell called keratinocytes to treat epidermolysis bullosa, a blistering skin disease with few treatments, they believe their findings may have implications for the derivation of other therapeutically useful tissue types. 

“For the first time, we were able to see how morphogens and master transcriptional regulators work together to make specific cell types,” said Anthony Oro, MD, PhD, professor of dermatology. “We’ve always wondered how a transcription factor required for the production of vastly different cell types knows which genes to make into proteins in which situation. Now we’ve answered that question: morphogens help the master transcription factors hook up to the right targets. Changing the concentration or type of morphogen, or even the order in which they are added to a cell, causes dramatically different outcomes.”

A paper describing the research was published online Nov. 5 in Nature Genetics. Oro, who is also the Eugene and Gloria Bauer Professor, is the senior author. Postdoctoral scholar Jillian Pattison, PhD; former postdoctoral scholar Sandra Melo, PhD; and graduate student Samantha Piekos share lead authorship.

Putting body parts in the right place

Morphogens are responsible for the body patterning that ensures, for example, that a fly’s wing ends up on its thorax rather than the top of its head. They were the first important class of proteins identified in the early days of developmental biology, in part because their effect on a developing embryo is so dramatic. Subsequent studies showed that they work through the process of diffusion and can have different effects based on their concentration throughout the embryo. Cells that are near other cells making and releasing the morphogen are exposed to a much higher concentration than those farther away; as waves of varying morphogens overlap and interact, they direct the proper placement of legs, wings and the head, for example. 

Soon, researchers also identified other types of proteins called master transcriptional regulators that bind to DNA to control the expression of specific genes throughout the cell. But they quickly learned that each of these regulators could spark the formation of vastly different cell types, and it was unclear how each regulator knew to favor the development of one tissue type over another. 

Oro and his colleagues were studying the effect of two well-known morphogens involved in skin development — BMP4 and retinoic acid — on the activity of a master transcriptional regulator called p63 that is responsible for tissue types as diverse as skin, thymus and the lining of the esophagus. 

In particular, they were interested in the process by which human embryonic stem cells can be triggered to develop into keratinocytes to form sheets of skin to repair the blistering and open wounds seen in people with epidermolysis bullosa. Previous attempts, although somewhat successful, yielded impure populations of cells that are difficult to use therapeutically. In search of a more reliable way to produce the cells, they wondered if they could generate keratinocytes by exposing the stem cells to a defined combination of morphogens and transcription factors. To do so, however, they experimented with when, and how much, of each component to add and watched how the cells reacted.  

Complex, synergistic feedback loop 

The researchers found that, although p63 is required to make skin cells from embryonic stem cells, it is not sufficient. In the absence of BMP4 or retinoic acid, nothing happens, even if p63 is snuggly bound to its landing pad on the DNA. However, when BMP4 or retinoic acid is added, the DNA conformation changes, and p63 begins transcribing skin-specific genes. This dependence of p63 activity on the presence of morphogens was unexpected and telling.

Making specific cell types is not a random event, and we can work to harness and accelerate this process to generate all kinds of transplantable tissues.

“Basically, p63 binds to the DNA, and then sits back and waits, twiddling its thumbs, until it is connected to specific genes by the morphogen-caused folding,” Oro said. “Or sometimes the DNA folds weeks or months in advance, and this foreshadowing sets up a particular differentiation plan, poising the chromatin to assume a specific fate when the transcriptional regulator is added.”

Additionally, the researchers discovered that exposing the stem cells to retinoic acid and BMP together also triggered the expression of p63, indicating a complex and synergistic feedback loop that controls skin development. 

“Now we have the tools necessary to understand how the DNA folds and unfolds in response to changing conditions,” Oro said. “Deciphering this chromatin origami is critical to learning how to make specific cell types for use in tissue replacement therapies. We know now that certain combinations and concentrations of morphogens cause the cells to fold their DNA in a certain way, while another stimulates the DNA to assume an entirely different conformation. Making specific cell types is not a random event, and we can work to harness and accelerate this process to generate all kinds of transplantable tissues.”

Additional Stanford authors are technicians Jessica Torkelson, Elizaveta Bashkirova and Hanson Hui Zhen; postdoctoral scholars Lingjie Li, PhD, and Xiaomin Bao, PhD; graduate students Adam Rubin and Maxwell Mumbach; undergraduates Eric Liaw, Daniel Alber and Charlotte Rajasingh; informatician Gautam Shankar; professor of dermatology and of genetics Howard Chang, MD, PhD; and professor and chair of dermatology Paul Khavari, MD, PhD. 

The research was supported by the California Institute for Regenerative Medicine, the National Institutes of Health (grants F32AR070565, AR45192, P50HG007735 and 5R00AR065490), the EB Research Partnership and the Howard Hughes Medical Institute

Stanford’s Department of Dermatology also supported the work.

Tagged with:

About author

Related Articles