Breaking News
November 18, 2018 - FDA Approves Aemcolo (rifamycin) to Treat Travelers’ Diarrhea
November 18, 2018 - Poverty blamed on widening north-south gap in young adult deaths in England
November 18, 2018 - Progress in meningitis lags far behind other vaccine-preventable diseases, analysis shows
November 18, 2018 - Consensus Statement Issued on Management of Foot, Ankle Gout
November 18, 2018 - Fine particle air pollution is a public health emergency hiding in plain sight
November 18, 2018 - In-hospital mortality higher among patients with drug-resistant infections
November 17, 2018 - Research shines new, explanatory light on link between obesity and cancer
November 17, 2018 - FIND explores new diagnostic assays for confirmatory HCV diagnosis in community settings
November 17, 2018 - Tracking Preemies’ Head Size May Yield IQ Clues
November 17, 2018 - Scientists call for unified standards in 3-D genome and epigenetic data
November 17, 2018 - Lab Innovations 2018 has beaten all records by attracting 3,113 attendees
November 17, 2018 - Sexuality education before age 18 may reduce risk of sexual assault in college
November 17, 2018 - Lab Innovations 2018 confirmed as a major hit with visitors, exhibitors and speakers
November 17, 2018 - Largest parasitic worm genetic study hatches novel treatment possibilities
November 17, 2018 - UCLA biologists uncover how head injuries can lead to serious brain disorders
November 17, 2018 - Static and dynamic physical activities offer varying protection against heart disease
November 17, 2018 - Obesity significantly increases risk of Type 2 diabetes and coronary artery disease
November 17, 2018 - People with rare cancers can benefit from genomic profiling, shows research
November 17, 2018 - NIH awards over $1.8 million to husband-and-wife doctors to test new breast cancer approach
November 17, 2018 - Four-in-one antibody used to fight flu shows promise in mice
November 17, 2018 - New approach allows pathogens to be starved by blocking important enzymes
November 17, 2018 - Higher body mass index could cause depression even without health problems
November 17, 2018 - Protein which plays role in sensing cell damage serves as new target to treat pulmonary hypertension
November 17, 2018 - FDA Approves Adcetris (brentuximab vedotin) in Combination with Chemotherapy for Adults with Previously Untreated Systemic Anaplastic Large Cell Lymphoma or Other CD30-Expressing Peripheral T-Cell Lymphomas
November 17, 2018 - ID specialist input improves outcomes for outpatient parenteral antimicrobial therapy
November 17, 2018 - UT Southwestern scientists selected to receive 2019 Edith and Peter O’Donnell Awards
November 17, 2018 - New clinical algorithm to help individuals manage type 2 diabetes when fasting during Ramadan
November 17, 2018 - Researchers identify LZTR1 as evolutionarily conserved component of RAS pathway
November 17, 2018 - Heart Disease Leading Cause of Death in Low-Income Counties
November 17, 2018 - Estrogen Levels Test: MedlinePlus Lab Test Information
November 17, 2018 - Research reveals link between immunity, diabetes
November 17, 2018 - Research shows how to achieve improved smoking cessation outcomes within California’s Medicaid population
November 17, 2018 - New study finds less understanding and implementation of patient engagement
November 17, 2018 - New shoe insole technology could help diabetic ulcers heal better while walking
November 17, 2018 - New method to extend cell division and immortalization of avian-derived cells
November 17, 2018 - Australian Academy of Science urges parents to vaccinate children against meningococcal disease
November 17, 2018 - Hot water treatment may help improve inflammation and metabolism in sedentary people
November 17, 2018 - Researchers produce 3D chemical maps of small biological samples
November 17, 2018 - Must Blood Pressure Rise Wth Age? Remote Tribes Hold Clues
November 17, 2018 - Noonan Syndrome
November 17, 2018 - Interventions to delay and prevent type 2 diabetes are underused, researchers say
November 17, 2018 - Hackathon prize winner seeks to remotely monitor patient skin conditions
November 17, 2018 - Research team identifies Ashkenazi Jewish founder mutation for Leigh syndrome
November 17, 2018 - Gene editing could be used to halt kidney disease in patients with Joubert syndrome
November 17, 2018 - Study uncovers link between gut disruption and aging
November 17, 2018 - Teens more likely to pick up smoking after exposure from friends and family
November 17, 2018 - Nicoya designate the Institute for Stem Cell Biology and Regenerative Medicine as the OpenSPR Centre of Excellence
November 17, 2018 - new horizon in dental, oral and craniofacial research
November 17, 2018 - How does poor air quality affect your health?
November 17, 2018 - New device can regulate children’s blood glucose more like natural pancreas
November 17, 2018 - Game-Changers in Western Blotting and Protein Analysis
November 17, 2018 - FDA announces new actions to limit sale of e-cigarettes to youth
November 17, 2018 - Warmer winter temperatures related to higher crime rates
November 17, 2018 - MCO places increasing emphasis on helping people find and access healthy food
November 17, 2018 - Group of students aim to improve malaria diagnosis using old smartphones
November 17, 2018 - Transplantation of feces may protect preterm children from deadly bowel disease
November 17, 2018 - Researchers explore whether low-gluten diets can be recommended for people without allergies
November 17, 2018 - New and better marker for assessing patients after cardiac arrest
November 17, 2018 - For 7-year-old with failing bone marrow, a life-saving transplant | News Center
November 17, 2018 - New first-line treatment for peripheral T-cell lymphoma approved by FDA
November 17, 2018 - Artificial intelligence could be valuable tool to help young victims disclose traumatic testimony
November 17, 2018 - Breakthrough in the treatment of Restless Legs Syndrome
November 16, 2018 - FDA Approves Keytruda (pembrolizumab) for the Treatment of Patients with Hepatocellular Carcinoma (HCC) Who Have Been Previously Treated with Sorafenib
November 16, 2018 - Eagle Books | Native Diabetes Wellness Program
November 16, 2018 - Patients with common heart failure more likely to have lethal heart rhythms
November 16, 2018 - How AI could help veterinarians code their notes | News Center
November 16, 2018 - Bias-based bullying does more harm to students than generalized bullying
November 16, 2018 - Researchers find first direct evidence that cerebellum plays role in cognitive functions
November 16, 2018 - Non-coding genetic variant plays key role in endothelial function and disease incidence
November 16, 2018 - EMA recommends first all-oral treatment to tackle deadly sleeping sickness
November 16, 2018 - Drug used to treat dizziness may slow down growth of triple-negative breast cancer
November 16, 2018 - AHA: Icosapent Ethyl Cuts CV Risk From Elevated Triglycerides
November 16, 2018 - ‘Orphan’ RNAs make cancer deadlier, but potentially easier to diagnose
November 16, 2018 - Air Cube touches down at hospital | News Center
November 16, 2018 - CRISPR-based tool shown to enhance cell-based immunotherapy
November 16, 2018 - Mechanisms that govern HIV latency differ in the gut and blood, finds study
November 16, 2018 - Researchers unravel mystery of NPM1 protein in acute myeloid leukemia
November 16, 2018 - High school students less likely to select milk, fruit for lunch when fruit juice is available
November 16, 2018 - Football coaches with great emotional competence are more successful
November 16, 2018 - Researchers awarded $10 million grant to address root causes of asthma in Puerto Rico
‘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