(Press-News.org) (Memphis, Tenn.—May 24, 2023) Like thread tightly wrapped around a spool, DNA is wrapped around histones and packaged into structures called nucleosomes. Scientists at St. Jude Children’s Research Hospital are exploring how a type of transcription factor called a pioneer transcription factor accesses DNA even when it is tightly wound. Their work revealed how the epigenetic landscape influences transcription factor binding. Problems with transcription have been implicated in numerous cancers, so this more detailed understanding of the process may aid in developing future therapeutics. The study was published today in Nature.
The nucleosome packaging of DNA can physically block transcription factors that regulate gene expression from accessing their binding sites. Restricting access to DNA is an integral part of how transcription is regulated. However, pioneer transcription factors can bind to their target piece of DNA even within compacted chromatin and are also known to promote the binding of other transcription factors.
Among pioneer transcription factors are the so-called Yamanaka factors which include Oct4 and are used to induce pluripotency (the ability to give rise to different cell types). How pioneer transcription factors access tightly wound DNA was unclear. To better understand the process, scientists at St. Jude used cryo-electron microscopy (cryo-EM) and biochemistry to investigate how Oct4 interacts with nucleosomes.
“Building on prior work to understand the dynamic behavior of nucleosomes, we wanted to understand how other factors might utilize those dynamic changes to access chromatin,” said corresponding author Mario Halic, Ph.D., St. Jude Department of Structural Biology. “Oct4 did not bind where we anticipated it might — rather than binding inside the nucleosome, we found that it bound a little bit outside.”
“One of the main findings is that epigenetic modifications can affect transcription factor binding and cooperativity,” Halic added. “The existing epigenetic state of chromatin can determine how transcription factors will cooperatively bind to chromatin.”
The epigenetic impact
Results show that the first Oct4 molecule binding "fixes" the nucleosome in a position that increases the exposure of other binding sites, thus promoting the binding of additional transcription factors and explaining transcription factor cooperativity. They also found that Oct4 contacts histones, and these interactions promote chromatin opening and influence cooperativity. Their work also showed that modifications at histone H3K27 affect the positioning of DNA by Oct4. These findings explain how the epigenetic landscape can regulate Oct4 activity to ensure proper cell programming.
Notably, the researchers used endogenous human DNA sequences instead of artificial sequences to assemble their nucleosomes. This allowed them to study the dynamic nature of the nucleosome, despite it being more challenging to work with.
“In this work, we used real genomic DNA sequences to study transcription factors in the context of where they function,” said first author Kalyan Sinha, Ph.D., St. Jude Department of Structural Biology. “This strategy allowed us to discover that the first binding event of Oct4 positions the nucleosomal DNA in a manner that allows cooperative binding of additional Oct4 molecules to internal sites. In addition, we observed exciting interactions with histone tails and have seen that histone modifications can alter those interactions. Together, these findings provide new insights into the pioneering activity of Oct4.”
“Histone modifications affect how DNA is positioned and how transcription factors can bind cooperatively,” Sinha added, “which means in cells, if you have the same DNA sequence, different epigenetic modifications can result in different, combinatorial effects on transcription factor binding.”
Authors and funding
The study’s other authors are Silvija Bilokapic, Yongming Du and Deepshikha Malik of St. Jude.
The study was supported by the National Institutes of Health (1R01GM135599-01 and 1R01GM141694-01) and ALSAC, the fundraising and awareness organization of St. Jude.
St. Jude Media Relations Contacts
Chelsea Bryant
Desk: (901) 595-0564
Cell: (256) 244-2048
chelsea.bryant@stjude.org
media@stjude.org
Emily Gest
Desk: (901) 595-0260
Cell: (901) 568-9869
emily.gest@stjude.org
media@stjude.org
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress blog, and follow St. Jude on social media at @stjuderesearch.
END
Epigenetic landscape modulates pioneer transcription factor binding
2023-05-24
[Attachments] See images for this press release:
ELSE PRESS RELEASES FROM THIS DATE:
A popular compostable plastic doesn’t break down in the ocean
2023-05-24
A widely used compostable plastic persists unchanged in marine environments for at least 14 months, according to a new study in the open-access journal PLOS ONE by Sarah-Jeanne Royer and colleagues from Scripps Institution of Oceanography at the University of California, San Diego. The study highlights the distinction between textile materials that can be composted in a controlled, industrial setting (PLA), and the ones that can undergo biodegradation in natural environments (cellulose-based textiles).
The accumulation and persistence of oil-based plastic waste ...
Physical activity linked to higher pain tolerance
2023-05-24
A new analysis of data from more than 10,000 adults shows that people who were physically active had higher pain tolerance than those who were sedentary, and that those with a higher level of activity had a higher level of pain tolerance. Anders Årnes of the University Hospital of North Norway, Tromsø, and colleagues present these findings in the open-access journal PLOS ONE on May 24, 2023.
Prior research has suggested the possibility that a habit of engaging in a higher level of physical activity might help ease or prevent chronic pain by boosting pain tolerance. However, most studies on this topic have been small or focused on narrow groups of people.
To help clarify the ...
U.S. teens who are food insecure are more likely to engage in emotional eating and consume sugar-sweetened beverages and junk foods
2023-05-24
Article URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0285446
Article Title: Psychosocial correlates in patterns of adolescent emotional eating and dietary consumption
Author Countries: USA
Funding: The authors received no specific funding for this work. END ...
Scientists provide first field observations of coccolithophore osmotrophy
2023-05-24
Coccolithophores, a globally ubiquitous type of phytoplankton, play an essential role in the cycling of carbon between the ocean and atmosphere. New research from Bigelow Laboratory for Ocean Sciences shows that these vital microbes can survive in low-light conditions by taking up dissolved organic forms of carbon, forcing researchers to reconsider the processes that drive carbon cycling in the ocean. The findings were published this week in Science Advances.
The ability to extract carbon from the direct absorption of dissolved organic carbon is known as osmotrophy. ...
Not so biodegradable: new study finds bio-based plastic and plastic-blend textiles do not biodegrade in the ocean
2023-05-24
Plastic pollution is seemingly omnipresent in society, and while plastic bags, cups, and bottles may first come to mind, plastics are also increasingly used to make clothing, rugs, and other textiles.
A new study from UC San Diego’s Scripps Institution of Oceanography, published May 24 in the journal PLOS One, for the first time tracked the ability of natural, synthetic, and blended fabrics to biodegrade directly in the ocean.
Lead author Sarah-Jeanne Royer conducted an experiment off the Ellen Browning Scripps Memorial Pier and found that natural and wood-based cellulose fabrics degraded within a month. Synthetic textiles, including so-called compostable ...
Increasing heat likely a major factor in human migration
2023-05-24
Rising temperatures due to climate change are likely influencing human migration patterns, according to a new study by Rita Issa of University College London and colleagues, published May 24 in the open-access journal PLOS Climate.
In the last decade, heatwaves were frequent, and surface temperatures were the warmest on record. As the planet warms, many people are expected to leave their homes to escape extreme temperatures. However, the exact role of heat in human migration is not yet understood. To illuminate this relationship, Issa’s team conducted a review of research documents, ...
Public health solutions to disrupt the US firearm crisis
2023-05-24
The epidemic of firearm injury and death in the USA is preventable, and the field of public health can offer practical solutions, argue Dr. Megan L. Ranney and colleagues in an opinion article in PLOS Global Public Health. Through harm reduction and community engagement programs, public health professionals, healthcare providers and community members can reduce the impact on individuals, families and communities.
Despite the attention school and public mass shootings in the US gain, they make up a minority of US firearm injuries and deaths. Most firearm deaths are from homicide and suicide: ...
Gender trumps politics in determining people’s ability to read others’ minds
2023-05-24
Political parties regularly claim to have their finger on the pulse and be able to read the public mood. Yet a new study challenges the idea that being political makes you good at understanding others: it shows gender, not politics, is a far more important factor in determining people’s social skills.
Analysis of a sample of 4,000 people from across the UK, compiled by a team of psychologists at the University of Bath, highlights that being female and educated are the biggest determinants of whether you can understand or read others’ ...
Georgia Tech researchers develop wireless monitoring patch system to detect sleep apnea at home
2023-05-24
The prevalence of sleep disorders, like sleep apnea, is on the rise in the U.S., but current protocols to conduct clinically accepted assessments are expensive and inconvenient.
Georgia Tech researchers have created a wearable device to accurately measure obstructive sleep apnea — when the body repeatedly stops and restarts breathing for a period — as well as the quality of sleep people get when they are at rest.
Under conventional methods, people who are suspected of having some sleep issue or disorder ...
How tasty is the food?
2023-05-24
To know when it’s time for a meal – and when to stop eating again – is important to survive and to stay healthy, for humans and animals alike. Researchers at the Max Planck Institute for Biological Intelligence investigated how the brain regulates feeding behavior in mice. The team found that the hormone ghrelin activates specialized nerve cells in a brain region known as the amygdala. Here, the interaction between ghrelin and the specialized neurons promotes food consumption and conveys ...