Breaking News
March 18, 2019 - Taking painkillers during pregnancy is not responsible for asthma risk in children, study shows
March 18, 2019 - Prediagnosis Psychiatric Care Linked to Worse Cancer Mortality
March 18, 2019 - Paris hospital halts stool study after donor deluge
March 18, 2019 - Partial oral antibiotic therapy shows efficacy and safety in patients with infectious endocarditis
March 18, 2019 - Olympus improves access to science education through BioBus collaboration
March 18, 2019 - Depression screening does not improve quality of life in heart attack patients
March 18, 2019 - Echocardiography may aid in patient selection for TMVR
March 18, 2019 - Are ‘Inactive’ Ingredients in Your Drugs Really So Harmless?
March 18, 2019 - Scientists tackle rare retinal disease in unique research project
March 18, 2019 - Death By A Thousand Clicks
March 18, 2019 - Absorbable, antibiotic-eluting envelope can reduce rate of cardiac device infections
March 18, 2019 - Hormonal treatment associated with depression in men with prostate cancer
March 18, 2019 - Porvair Sciences launches reinforced 96-well deep round microplate
March 18, 2019 - Simplified catheter ablation could slash waiting lists for atrial fibrillation patients
March 18, 2019 - BFR therapy as part of rehabilitation following ACL surgery may slow bone loss
March 18, 2019 - A human model to test implants for cataract surgery
March 18, 2019 - New risk adjustment model could reduce financial penalty for safety net hospitals
March 18, 2019 - NHS cancer patients’ wait to start treatment worrying
March 18, 2019 - Inventiva Announces Results from Phase IIb Clinical Trial with Lanifibranor in Systemic Sclerosis
March 18, 2019 - Cologuard
March 18, 2019 - Researchers find evidence of prenatal environment tuning genomic imprinting
March 18, 2019 - Dolomite Bio launches novel Nadia product family for single-cell research
March 18, 2019 - Intellipharmaceutics Announces Resubmission of New Drug Application to the U.S. FDA for its Oxycodone ER
March 18, 2019 - Excessive gestational weight gain tied to maternal morbidity
March 18, 2019 - RCEM issues position statement on metrics to supplement four-hour standard target
March 17, 2019 - Noncontrast Brain MRI Effective for Monitoring Multiple Sclerosis
March 17, 2019 - Brain region plays key role in regulation of parenting behavior, study finds
March 17, 2019 - Natural speed limit on DNA replication sets pace for life’s first steps
March 17, 2019 - New research reveals overlooked impact of herbicide glyphosate on the environment
March 17, 2019 - Molecular patterns could help predict relapse risk in breast cancer patients
March 17, 2019 - Study confirms sensitivity of microbiological cultures for detecting cholera
March 17, 2019 - Scientists Spot Clues to Predicting Breast Cancer’s Return
March 17, 2019 - Scientists identify gene that keeps PTSD-like behavior at bay in female mice
March 17, 2019 - New method would allow doctors to detect earliest stages of cancers in the lymph nodes
March 17, 2019 - Cholesterol protein discovery raises hope for smarter drugs
March 17, 2019 - New insect medium delivers high viable cell density growth and protein yield
March 17, 2019 - Opioid crisis brings concerns about heart dangers
March 17, 2019 - Resistance Training May Prevent Type 2 Diabetes Progression
March 17, 2019 - Bioluminescence sensors make new approaches to drug discovery possible
March 17, 2019 - New FDA Rules Aim to Keep Kids From Flavored E-Cigarettes
March 17, 2019 - Vitamin B3 analogue boosts production of blood cells
March 17, 2019 - Government cuts to stop smoking services have detrimental impact on public health
March 17, 2019 - Common tool to assess potential adoptive parents lags behind societal changes
March 17, 2019 - Patients’ own cells could be the key to treating Crohn’s disease
March 17, 2019 - Diagnostic delays common in inflammatory bowel disease
March 17, 2019 - Study uncovers dramatic differences in the brains of Hispanics with dementia
March 17, 2019 - Study describes epigenetic loss that changes how cells obtain energy from cancer
March 16, 2019 - Active Bathing in Non-ICU Setting Does Not Cut Infections
March 16, 2019 - How the immune system maintains a healthy gut microbiota
March 16, 2019 - Bacteria ‘trap’ could help in the fight against antimicrobial resistance
March 16, 2019 - Hospital work environment associated with all EHR usability outcomes
March 16, 2019 - Study unravels mystery behind how the brain encodes time when forming long-term memories
March 16, 2019 - Light physical activity may lower risk of cardiovascular disease in older women
March 16, 2019 - USP15 enzyme could potentially lead to new treatments for breast, pancreatic cancer
March 16, 2019 - After Chinese Infant Gene-Editing Scandal, U.S. Health Officials Join Call for a Ban
March 16, 2019 - PACS1 syndrome – Genetics Home Reference
March 16, 2019 - Researchers discover an unexpected organization of antimicrobial molecules that amplifies immune response
March 16, 2019 - With New Study, Era of Open-Heart Surgery for Aortic Stenosis May be Ending
March 16, 2019 - Dolomite Bio introduces high throughput sNuc-Seq protocol for its Nadia Instrument
March 16, 2019 - New course prepares materials scientists for biomedical testing
March 16, 2019 - Finding clues to a functional HIV cure
March 16, 2019 - People with chronic periodontitis have higher risk for dementia
March 16, 2019 - Few heart care recommendations are based on rigorous study
March 16, 2019 - Colorectal cancer diagnosed at early age is distinct from that in older patients
March 16, 2019 - Researchers use MRI and AI techniques at birth to predict cognitive development at age 2
March 16, 2019 - Discarding information from the brain linked to more mental effort, finds study
March 16, 2019 - OTA International supplement provides current snapshot and forward look at global trauma systems
March 16, 2019 - NIH trial to track outcomes of liver transplantation from HIV+ donors to HIV+ recipients
March 16, 2019 - Apple Heart Study shows how wearable technology can help detect heart problem
March 16, 2019 - Researchers determine factors that cause stress development in the human body
March 16, 2019 - Elderly Men Undertreated for Osteoporosis
March 16, 2019 - People with chronic pain are coping with the help of Pinterest, new study reveals
March 16, 2019 - New study could reveal the complex interaction between languages and human beings who use them
March 16, 2019 - Tufts engineers develop new tool to identify metabolic signatures linked to disease
March 16, 2019 - New proteomics-based test could aid in early detection of ovarian cancer
March 16, 2019 - New research opens possibility of using sperm taken from testicles to overcome infertility
March 16, 2019 - Scientists find new proof that narcolepsy is an autoimmune disease
March 16, 2019 - FDA OKs a New Generic of the Blood Pressure Drug Valsartan to Ease Shortage Due to Recalls
March 16, 2019 - Eliminating smoking and obesity could affect racial health disparities
March 16, 2019 - Wearable tracking device achieves higher accuracy in position tracking using thermal sensors
‘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