Genetic scissors helping cancer research: Removing individual binding sites for the MYC oncogene can slow down cancer cell growth
Researchers in the Taipale lab have identified a mechanism by which an oncogene commonly activated in cancer patients affects the growth rate of cells. In the future, the findings can help in developing new treatments that could prevent cancer genes from inducing tumor growth.
Article: Pihlajamaa et al., Nature Biotechnology 41:197–203, 2023
Related in the media: MedicalXpress
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A study uncovers the grammar behind human gene regulation
Gene regulation is an important process that controls the activity of genes in cells. Incorrect gene regulation can contribute to the onset of many diseases, including cancer. The DNA of the human genome contains genes that code for proteins, which in turn give muscle cells their strength and brain cells their ability to process information. DNA also contains gene regulatory elements that determine when and where genes are expressed – so that muscle genes are expressed in muscles and brain genes in the brain.
However, the regulatory code that determines gene activity remains poorly understood. Even though the human genome comprises almost three billion base pairs, it is too short for learning the gene regulatory code from the genomic sequence alone. The problem is similar to that faced by a linguist who tries to understand a forgotten language on the basis of a few short texts. The Taipale lab has now found a way around this problem, by measuring the gene regulatory activity from a collection of DNA sequences that together are 100 times larger than the entire human genome.
Article: Sahu et al., Nature Genetics 54:283-294, 2022
Related in the media: Phys.org
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Scientists develop a speedy new method to analyze thousands of noncoding variants and their links to disease
Scientists of the Taipale lab developed a novel high-throughput biological assay, SNP-SELEX, to accelerate analysis of noncoding variants. The work was done in collaboration with the laboratory of Bing Ren (UCSD), and the lead author of the study, Jian Yan, a Taipale lab alumni who is now a professor at the City University of Hong Kong and China’s Northwest University. The SNP-SELEX method can be used to rapidly measure the binding between the transcription factors and hundreds of thousands of human non-coding variant sequences. As a proof of principle, the researchers studied variants from regions of the genome linked to type II diabetes. Out of 270 transcription factors and nearly 100,000 variants, they found a noncoding variant that impacted the DNA binding of a transcription factor important for diabetes.
Article: Yan et al., Nature 591:147-151, 2021
Related in the media: MedicalXpress, AsianScientist
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Scientists map the binding specificity of human RNA-binding proteins
RNA-binding proteins (RBPs) regulate RNA metabolism at multiple levels by affecting splicing of nascent transcripts, RNA folding, base modification, transport, localization, translation, and stability. Despite their central role in RNA function, the RNA-binding specificities of most RBPs remain unknown or incompletely defined. To address this, we have assembled a genome-scale collection of RBPs and their RNA-binding domains (RBDs) and assessed their specificities using high-throughput RNA-SELEX (HTR-SELEX). Our work represents the largest systematic resource for the analysis of human RBPs and will greatly facilitate future analysis of the various biological roles of this important class of proteins.
Article: Jolma et al., Genome Research 30:962-973, 2020
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Reading the DNA book without opening it
Every human cell contains around two meters of DNA. In order for this to fit inside the microscopic space of a cell nucleus it has to be packaged very tightly. Protein ‘reels’, called histones, enable DNA to be condensed into a much smaller volume through the formation of structures called nucleosomes. In each nucleosome, DNA is wrapped neatly around the histones almost twice, in a manner similar to a garden hose being wound up around a reel. Although this process allows DNA to be packaged into the nucleus, it causes the DNA within nucleosomes to be inaccessible, which was previously thought to prevent instructions within DNA from being ‘read’ by other molecules without unwinding the DNA first. Scientists of Taipale and Patrick Cramer (Max Planck, Göttingen) laboratories analyzed binding of more than 200 transcription factors to nucleosomal DNA, identifying five distinct modes by which transcription factors can interact with the nucleosome, without completely unwinding it. In a follow-up work, the scientists also solved the structure of important ‘Pioneer’ transcription factors SOX2 and SOX11 bound to a nucleosome, explaining how nucleosomal DNA can be recognized and nucleosomes displaced to facilitate transcription. These findings are important for understanding how the two major protein types that bind to DNA, histones and sequence-specific transcription factors interact with each other, and pave the way for understanding of gene regulation based on biochemical principles.
Articles: Zhu et al., Nature 562:76-81, 2018; Dodonova et al., Nature 580:669-672, 2020
Review article: Morgunova and Taipale, Current Opinion in Structural Biology 71:171-179, 2021.
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The popular genome editing tool CRISPR causes a DNA damage response
Researchers at Cambridge University and Karolinska Institutet have found that DNA double-stranded breaks created by the genome editing tool CRISPR-Cas9 activate the tumor suppressor protein p53. p53 normally functions as the guardian of the genome, protecting cells against DNA damage that can lead to cancer. The researchers also found that inhibition of p53 increased efficiency of precision genome editing. The results suggest that controlling the DNA damage response will be important in developing the next generation of safe and efficient genome editing technologies.
Article: Haapaniemi et al., Nature Medicine 24:927-930, 2018
Related in the media: New York Times, Medical News Today, Nature Medicine
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Professor Jussi Taipale joins the Department of Biochemistry, University of Cambridge as the new Herchel Smith Professor of Biochemistry
Professor Jussi Taipale will continue his work in Cambridge on transcriptional regulation; specifically to understand how DNA sequences determine where and when genes are expressed via the binding of transcription factors:
“Our understanding of the regulation of gene expression is very conceptual and at a high level of abstraction. It’s equivalent to knowing that Spanish is composed of letters and words, and that Spanish sentences have an object, a subject, a verb, and so on. My conceptual understanding of the Spanish language is therefore very good, as is our understanding of the regulation of a few specific genes, but I cannot speak a word of Spanish. What we’re trying to do for gene expression is work out the lexicon and the grammar. This cannot be done by studying a few specific genes; it’s fundamentally a systems-level problem, which requires systems biology and global approaches to solve.“
Understanding the lexicon and grammar of gene expression will support the Taipale Group in their second systems-level research area of elucidating control of tissue and organism growth, which is likely to be found in gene regulatory elements. Professor Taipale’s research will impact on both our fundamental understanding of the regulation of gene expression, and on our knowledge of the mechanisms controlling cell growth during normal development and in pathologies such as cancer.
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Jussi Taipale elected as Fellow of the European Academy of Cancer Sciences
The Academy, launched in 2009, is an independent advisory body of eminent oncologists and cancer researchers, placing science at the core of policies to sustainably reduce the death and suffering caused by cancer in Europe.
Academy Fellows are responsible for defining the overall objectives of the Academy and addressing issues such as credibility of the institution as well as interacting with EU institutions to facilitate proposals and implementation of new policies that ensure that cancer remains at the top of the European health and research agenda.
Most importantly, the European Academy of Cancer Sciences aims to collectively address the societal challenge that cancer is posing in Europe at large.
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Complex grammar of the genomic language
A new study from Sweden’s Karolinska Institutet shows that the ‘grammar’ of the human genetic code is more complex than that of even the most intricately constructed spoken languages in the world. The findings, published in the journal Nature, explain why the human genome is so difficult to decipher – and contribute to the further understanding of how genetic differences affect the risk of developing diseases on an individual
level.
Article: Jolma et al., Nature 527:384-388, 2015
Related in the media: Nature Reviews Genetics, Medical News Today, Phys.org, EurekAlert!
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New mutational patterns in gastrointestinal tract cancers
Mutations that lead to cancer are not only occurring in the 2 percent of the DNA that encodes for proteins, but also in the non-coding regions. These regions are determining when and where the genes are expressed. In the largest cancer genome study performed in the Nordic countries, researchers lead by Professors Jussi Taipale and Lauri Aaltonen, studied more than two hundred whole genomes from colorectal cancer samples and detected a distinct accumulation of mutations at sites where the proteins CTCF and cohesin bind to the DNA.
Article: Katainen et al., Nature Genetics 47:818-821, 2015
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Language of gene switches unchanged across evolution
The language used in the switches that turn genes on and off has remained the same across millions of years of evolution, according to a new study led by researchers at Karolinska Institutet in Sweden. The findings, which are published in the scientific journal eLife , indicate that the differences between animals reside in the content and length of the instructions that are written using this conserved language.
Article: Nitta et al., eLife 4:e04837.001, 2015
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Jussi Taipale awarded grant for distinguished professors
The Grant for Distinguished Professors (Rådsprofessur) was awarded by the Swedish Research Council for the first time. The purpose of the Distinguished Professor program is to create conditions for the most distinguished researchers to conduct long-term research of great potential that involves considerable risk-taking. A total of 9 grants have been awarded, from 301 applicants. Each grant is 5 million SEK per year for 10 years.
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New mechanism behind prostate cancer
Work in the Taipale group at Karolinska Institutet, and in Gong-Hong Wei’s group in Biocenter Oulu, Finland has identified a mechanism affecting risk of prostate cancer. The researchers found how a particular inherited sequence variant contributes to a genetic program that drives prostate cancer growth and metastasis. The study opens up new directions in understanding how inherited genetic variation can cause elevated risk for prostate cancer and other human diseases.
Article: Huang et al. Nature Genetics 46:126-135, 2014
Related in the media: Science Daily, Nature Genetics
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Cell memory mechanism discovered
Scientists at Taipale group at the Karolinska Institutet have discovered that a ring-shaped protein called cohesin functions to facilitate cellular memory. The cells in our bodies can divide as often as once every 24 hours, creating a new, identical copy. DNA binding proteins called transcription factors are required for maintaining cell identity. They ensure that daughter cells have the same function as their mother cell, so that for example muscle cells can contract or pancreatic cells can produce insulin. However, each time a cell divides the specific binding pattern of the transcription factors is erased and has to be restored in both mother and daughter cells. The new work sheds light on how this happens, and also reveals that the cohesin could function as an indicator of which DNA sequences might contain disease-causing mutations.
Article: Yan et al. Cell 154:801-813, 2013
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Learning the alphabet of gene control
Scientists at Karolinska Institutet in Sweden and the University of Helsinki in Finland have made a large step towards understanding of how human genes are regulated. In a study, published in Cell, they identified the DNA sequences that bind to over four hundred proteins that control expression of genes. This knowledge is required for understanding of how differences in genomes of individuals affect their risk to develop disease.
Article: Jolma et al. Cell 152:327-339, 2013
Related in the media: Medical News Today