Further translation of the language of the genome

 

New research has uncovered more about the complexity of human gene regulation by identifying certain sequences of proteins called transcription factors that bind to DNA and regulate the expression of human genes.

Published today (9 April) in Nature, researchers from the Wellcome Sanger Institute, the University of Cambridge and their collaborators explored how DNA-guided transcription factors interact with each other.

This research adds to the groundwork of understanding the complex language of the gene regulatory code, and how DNA sequence patterns located close to our genes influence human development and disease risk.

Each gene has a regulatory region that contains instructions on when and where the gene is expressed. This information is written in a code that is read by transcription factors, which bind to specific DNA sequences and either increase or decrease the gene's expression.

Previous research has explored the 'language' of the genome -- the regulatory code that controls gene expression. It found that cooperation between multiple transcription factors is a key feature of transcription factor-DNA binding, with DNA actively facilitating interactions between various transcription factors.¹ With the regulatory code being far more complex than the genetic code, which explains how DNA sequence determines the structure of proteins, researchers are aiming to understand the regulatory language in more detail, focusing on the 'words' and 'grammar' -- such as the transcription factors -- that influence when and where genes are expressed.

This deeper understanding is crucial for uncovering how cells develop into specific types, how organs form and where they are located in the body during embryonic development, and for understanding what goes wrong in disease.

The interactions between transcription factors guided by DNA are poorly understood. In a new study, researchers from the Sanger Institute and the University of Cambridge used two novel algorithms to analyse 58,000 pairs of transcription factors from human cells. They did this to identify how and where transcription factors interact with each other to bolster their understanding of the genomic language.²

The researchers' results reveal new patterns and preferences in how certain transcription factors interact with each other -- also known as 'motifs'. In this study, the researchers estimate that they identified between 18 and 47 per cent of all human transcription factor pair motifs, greatly adding to their understanding of the regulatory code.

The team found that certain motifs they identified are present in developmental enhancers -- DNA regulatory elements that activate transcription of a gene -- that control important stages such as development of fingers. For example, the research notes that certain sequences of transcription factor motifs, or 'words' in the language, influence whether or not someone develops polydactyly -- too many fingers -- or syndactyly -- a fusion of fingers.

The findings also have implications for how scientists will use computational models -- such as artificial intelligence -- to predict protein structures in the future. Whilst these tools can predict the overall structure, they often cannot look into smaller details, such as how transcription factors interact with each other on DNA. These small interactions can have a big impact on human development, but computational models cannot always predict this. The researchers hope that future models will be able to incorporate the more minute transcription factor details to better predict protein structure and protein-DNA interactions.

This research marks a step forward in studying the smaller 'words' in the language of gene expression. By identifying small but key motifs in the genome, this research will help scientists understand and interpret the mechanisms influenced by transcription factors, particularly in the non-coding regions of the genome. These regions -- which make up 99 per cent of the genome -- do not code for proteins but still play a significant role in regulation of gene expression, and risk for development of disease.

Dr Ilya Sokolov, an author of the study at the Wellcome Sanger Institute, said: "By gaining a deeper understanding of how transcription factors interact when guided by DNA, we hope our research will shed light on the molecular basis of the regulatory code, particularly in the context of developmental disorders. These interactions are evolutionarily conserved across mammals and offer several advantages in development, from incorporating positional information to creating sharper gene expression responses. With advanced insights into the regulatory code, we are excited to help drive future research that will improve our understanding of human development and developmental disorders."

Professor Jussi Taipale, senior author of the study and Group Leader at the Wellcome Sanger Institute, said: "The human genome's regulatory code is very complex, far more complex than the genetic code, and this research into transcription factor interactions unlocks deeper insights into the 'language' of the genome. Not only does our study provide more information into patterns of human development but it paves the way for future work with computational models that can hopefully incorporate these new data to better understand gene regulation."

Notes

1. Arttu Jolma, Yimeng Yin, Kazuhiro R. Nitta, Kashyap Dave, Alexander Popov, Minna Taipale, Martin Enge, Teemu Kivioja, Ekaterina Morgunova, Jussi Taipale.(2015) 'DNA-dependent formation of transcription factor pairs alters their binding specificity.'Nature. DOI: 10.1038/nature15518
2. The researchers expressed a set of human transcription factors -- enriched in proteins that are conserved in mammals -- in Escherichia coli, combined them into a total of 58,754 transcription factor (TF) pairs and analysed their interactions by CAP-SELEX -- consecutive affinity purification evolution of ligands by exponential enrichment. CAP-SELEX is a method which enables the discovery of TF-TF-DNA binding preferences.

Journal Reference:

1. Zhiyuan Xie, Ilya Sokolov, Maria Osmala, Xue Yue, Grace Bower, J. Patrick Pett, Yinan Chen, Kai Wang, Ayse Derya Cavga, Alexander Popov, Sarah A. Teichmann, Ekaterina Morgunova, Evgeny Z. Kvon, Yimeng Yin, Jussi Taipale. DNA-guided transcription factor interactions extend human gene regulatory code. Nature, 2025; DOI: 10.1038/s41586-025-08844-z 

Courtesy:

Wellcome Trust Sanger Institute. "Further translation of the language of the genome." ScienceDaily. ScienceDaily, 9 April 2025. <www.sciencedaily.com/releases/2025/04/250409155027.htm>.

 

 

 

 

Novel drug delivery platform paves way to potential new treatments for Alzheimer's, other brain-related disorders

 

Oregon State University researchers have discovered a way to get anti-inflammatory medicine across the blood-brain barrier, opening the door to potential new therapies for a range of conditions, including Alzheimer's disease, multiple sclerosis, Parkinson's disease and cancer cachexia.

The delivery method involves specially engineered nanoparticles, tiny bits of matter no larger than 100 billionths of a meter.

Tested in a mouse model, the dual peptide-functionalized polymeric nanocarriers reached their intended destination, the hypothalamus, and delivered a drug that inhibits a key protein associated with inflammation.

"Our work presents a significant breakthrough," said Oleh Taratula, professor in the OSU College of Pharmacy.

Findings were published today in Advanced Healthcare Materials.

The hypothalamus is a small but vital part of the brain situated below the thalamus and above the brainstem, and it plays a key role in maintaining homeostasis -- the body's internal balance. It regulates body temperature, manages sleep cycles, hormone production and emotional responses, and controls hunger and thirst.

In this study, researchers specifically looked at the hypothalamus as it pertains to cachexia, a deadly weight-loss condition associated with cancers of the ovaries, stomach, lungs and pancreas and other chronic conditions such as renal failure, cystic fibrosis, Crohn's disease, rheumatoid arthritis and HIV.

People with cancer cachexia will lose weight even if they eat, and not just fat but muscle mass as well. The debilitating syndrome affects up to 80% of advanced cancer patients and kills as many as 30% of the cancer patients it afflicts.

"Inflammation of the hypothalamus plays a pivotal role in dysregulating those patients' appetite and metabolism," Taratula said. "As cachexia progresses, it significantly impacts quality of life, treatment tolerance and overall survival chances."

The systemic delivery of anti-inflammatory agents, including the IRAK4 inhibitors used in this research, to the hypothalamus presents significant challenges, Taratula said, mainly because of the restrictive nature of the blood-brain barrier.

The blood-brain barrier, often referred to as the BBB, is a protective shield separating the brain from the bloodstream. The BBB is made up of tightly packed cells lining the blood vessels in the brain and controls what substances can move from the blood to the brain.

It allows essential nutrients like oxygen and glucose to pass through and blocks harmful substances such as toxins and pathogens, keeping the brain safe from infections and damage. But it can also deny entry to therapeutic agents.

"An additional hurdle, even if you can get through the BBB to the hypothalamus, is hitting the bullseye within the hypothalamus -- the activated microglia cells that act as key mediators of inflammation," Taratula said. "Our nanocarriers show a dual-targeting capability, and once in the microglia, drug release is triggered by elevated intracellular glutathione levels. We demonstrated, for the first time, that nanocarriers can successfully deliver an IRAK4 inhibitor to the hypothalamus of mice with cancer cachexia."

The scientists observed substantial reductions in key inflammatory markers in the hypothalamus, and the nanocarriers led to a 94% increase in food intake and significantly preserved body weight and muscle mass. And the implications extend far beyond cancer cachexia, Taratula added.

"The nanoplatform's ability to deliver therapeutics across the BBB and target microglia opens new possibilities for treating neurological conditions characterized by brain inflammation, including Alzheimer's disease and multiple sclerosis," he said.

Taratula was joined in the study by College of Pharmacy colleagues Yoon Tae Goo, Vladislav Grigoriev, Tetiana Korzun, Kongbrailatpam Shitaljit Sharma, Prem Singh and Olena Taratula, and by Daniel Marks from Endevica Bio.

The National Cancer Institute of the National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Research Foundation of Korea funded the research.

Journal Reference:

1. Yoon Tae Goo, Vladislav Grigoriev, Tetiana Korzun, Kongbrailatpam Shitaljit Sharma, Prem Singh, Olena R. Taratula, Daniel L. Marks, Oleh Taratula. Blood‐Brain Barrier‐Penetrating Nanocarriers Enable Microglial‐Specific Drug Delivery in Hypothalamic Neuroinflammation. Advanced Healthcare Materials, 2025; DOI: 10.1002/adhm.202500521 

Courtesy:

Oregon State University. "Novel drug delivery platform paves way to potential new treatments for Alzheimer's, other brain-related disorders." ScienceDaily. ScienceDaily, 9 April 2025. <www.sciencedaily.com/releases/2025/04/250409115422.htm>.

 

 

 

 

Driving the CAR to fight acute myeloid leukemia

One main goal of anti-cancer therapies is to kill tumor cells without affecting the surrounding normal cells. Therefore, many drugs are designed to target tumor-specific antigens, which are molecules only expressed by cancer cells. However, it has proven difficult to identify such specific antigens in certain cancer types, including acute myeloid leukemia (AML).

AML patients are often treated using allogeneic hematopoietic stem cell transplantation (allo-HCT), where they receive stem cells from a donor.

Unfortunately, despite advancements with allo-HCT, many AML patients relapse.

In a recent article published in Nature Cancer, a multi-institutional research team led by The University of Osaka describes how a molecule called HLA-DRB1 can be used as a target for chimeric antigen receptor (CAR)-based therapy for AML.

In CAR-based therapy, T cells are engineered to target and kill cells that express a specific molecule.

CAR T cells have been highly successful in individuals with B cell leukemia/lymphoma and multiple myeloma (MM). However, most of the CAR T cell targets currently in clinical trials for AML are also expressed in normal cell types, leading to potential toxicity.

"In our previous work in MM, we screened monoclonal antibodies (mAbs) to identify any that could react with human MM samples but not with normal blood cells," says Shunya Ikeda, lead author of the study.

"We aimed to use that same strategy to find AML-specific antigens."

The team began screening thousands of mAbs raised against AML cells, narrowing this list down to 32 that bind specifically to AML cells.

One mAb, named KG2032, clearly bound to AML cells in over 50% of patient samples tested.

Using a sequencing strategy, the researchers determined that KG2032 bound to HLA-DRB1.

"Interestingly, we found that KG2032 reacted with a specific HLA-DRB1 subset in which the protein has an amino acid other than aspartic acid in the 86^th position," explains Naoki Hosen, senior author of the article.

"KG2032 would therefore only be reactive to AML cells in individuals with mismatched HLA-DRB1, meaning the patient carries this amino acid residue but the allo-HCT donor does not."

This finding indicates that HLA-DRB1 can be a potential target in treating certain patients with AML who have relapsed after allo-HCT.

The team then engineered KG2032 CAR T cells without the reactive HLA-DRB1 allele to test this finding. 

The KG2032 CAR T cells displayed strong and specific anti-AML effects in vitro with cell culture experiments, as well as in vivo with a mouse model.

The treated mice did not display any overt signs of toxicity.

Engineered cord blood-derived CAR natural killer (NK) cells showed similar results.

Overall, these very promising findings indicate that KG2032-derived CAR T or NK cells may be a lifesaving intervention for AML patients who have relapsed following allo-HCT. Clinical trials are currently being planned for both cell types.

Journal Reference:

1. Shunya Ikeda, Kana Hasegawa, Yosuke Kogue, Takao Arimori, Ryuhei Kawamoto, Tansri Wibowo, Moto Yaga, Yuri Inada, Hirofumi Uehara, Miwa Matsubara, Mana Tachikawa, Makiko Suga, Shuhei Kida, Kumi Shibata, Kazuhito Tsutsumi, Kentaro Fukushima, Jiro Fujita, Tomoaki Ueda, Shinsuke Kusakabe, Akihisa Hino, Michiko Ichii, Asao Hirose, Hirohisa Nakamae, Masayuki Hino, Takafumi Nakao, Megumu Inoue, Kyoko Yoshihara, Satoshi Yoshihara, Shuji Ueda, Tetsuro Tachi, Hideki Kuroda, Koki Murakami, Noriyuki Kijima, Haruhiko Kishima, Eri Igashira, Mari Murakami, Tsuyoshi Takiuchi, Tadashi Kimura, Takashi Hiroshima, Toru Kimura, Yasushi Shintani, Chihaya Imai, Kosuke Yusa, Ryota Mori, Takayuki Ogino, Hidetoshi Eguchi, Kiyoshi Takeda, Yusuke Oji, Atsushi Kumanogoh, Junichi Takagi, Naoki Hosen. CAR T or NK cells targeting mismatched HLA-DR molecules in acute myeloid leukemia after allogeneic hematopoietic stem cell transplant. Nature Cancer, 2025; DOI: 10.1038/s43018-025-00934-1 

Courtesy:

Osaka University. "Driving the CAR to fight acute myeloid leukemia." ScienceDaily. ScienceDaily, 11 April 2025. <www.sciencedaily.com/releases/2025/04/250411112928.htm>.