Exploring the New Insights Revealed by Epigenetics
This article explores some of the recent research where epigenetic approaches have advanced our understanding of disease.
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Epigenetics, literally meaning “above” genetics, studies chemical modifications to DNA that do not change the DNA sequence itself, but influence gene expression.
These chemical modifications, including methylation of DNA bases and methylation or acetylation of histones, are reversible and change throughout our lives.
This article explores some of the recent research where epigenetic approaches have advanced our understanding of disease.
Epigenetic changes are enough to cause cancer
Although the influence of epigenetics on cancer development has been studied, cancer is primarily thought of as a genetic disease.
In a study published in Nature, a research team illustrated for the first time that epigenetic changes alone are enough to drive tumorigenesis.
They identified that dysregulation of Polycomb group proteins – which are epigenetic factors involved in repressing developmental genes – are associated with cell fate changes and cancer.
In Drosophila models, constant RNA interference knock-down of Polycomb genes triggered tumor formation. The researchers also found that transient depletion of Polycomb group proteins was enough to initiate cancer growth that persisted even after levels of the Polycomb group proteins were restored.
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway – known to induce the expression of cancer-related regulators – was irreversibly activated following the loss of Polycomb group proteins, leading to sustained cell growth, proliferation and cell migration.
This study illustrates the importance of discriminating the epigenetic contributions to tumorigenesis from the genetic, although further work is needed to address fully how this translates to the development and progression of human cancers.
Newly discovered role of epigenetic factors in brain folding
Epigenetics also plays an important role in determining cell fate in the brain as it folds, a new study has revealed.
Cortical folding is a critical process during development – it increases cortical surface area and brings functionally related and highly interconnected areas of the brain closer together.
It is crucial for higher cognitive functions, and malformation of the gyri (ridges) and sulci (depressions) can result in cognitive defects.
The stereotypical pattern of gyri and sulci that we think of when we picture the brain is predefined by a transcriptomic protomap – where sections of the brain have different levels of gene transcription, leading to expansion and folding in some areas, and other areas proliferate less to form fissures. But how the protomap is defined, implemented and initiated isn’t clear.
New research published in Science Advances has shown when the transcriptomic protomap is initiated and highlighted some of the cell fate signaling pathways involved.
By profiling both the epigenome and the transcriptome at high temporal and spatial resolution, the researchers identified a number of genes that had different transcription levels in gyri and a sulci, caused by changes to the epigenome. Of these, the researchers focused on a transcription factor called Cux2, that is known to control the proliferation of neural precursor cells.
When Cux2 was overprescribed in ferret brain cells, the pattern of cortical folds was modified, and when Cux2 was overprescribed in mice – which have smooth brains – folds formed in the cortex.
The research has illustrated how epigenetic regulation of transcription factors, namely Cux2, can initiate cortical folding.
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Epigenetic risk factors for ALS
Amyotrophic lateral sclerosis (ALS) is a complex disease, where in many cases, the exact cause cannot be identified.
Studies have suggested the identities of particular genes that may confer a higher risk for ALS, but researchers believe there are more risk factors that have yet to be uncovered.
The genetic variants that drive ALS development are hard to identify as each patient may only carry a few of the variants that confer risk, meaning analysis of large patient numbers is needed.
Recently, a team from Massachusetts Institute of Technology have analyzed the epigenome of motor neurons derived from the induced pluripotent stem cells of 380 ALS patients.
The researchers identified that a known subtype of ALS has a distinct epigenetic signature and pinpointed 30 epigenetic modifications that appeared to be linked to slower disease progression.
The modifications were located near genes related to the cellular inflammatory response, and the team aims to understand how these genes influence ALS progression in further research.
This research is also important for drug discovery efforts and may lead towards a more personalized approach to treating the condition.
“Mini guts” link epigenetic differences to Crohn’s disease
Crohn’s disease is a form of inflammatory bowel disease characterized by inflammation of the digestive tract. It causes symptoms that affect the quality of life, from stomach pain to weight loss and fatigue. Treatment options include surgery to remove part of the digestive tract of medications to reduce and prevent inflammation.
There has been limited success so far in identifying genetic risk factors for Crohn’s disease, and despite decades of research, there’s no known cause.
New research has taken stem cells from the guts of people with Crohn’s disease, ulcerative colitis and unaffected people, using these cells to grow 300 “mini guts” or organoids.
By analyzing the epigenetic profile of epithelial cells from the organoids, the researchers identified that epithelial cells from Crohn’s disease patients have a different epigenetic pattern compared to people without the condition.
They also identified that the DNA methylation changes cause an increase in major histocompatibility complex (MHC) class 1 expression, leading to increased inflammation in specific parts of the gut.
Epigenetic changes and disease severity were found to be correlated, which could help to provide insight into why the disease course can vary from patient to patient. The epigenetic changes are stable, which could further explain why Crohn’s disease symptoms can recur after treatment. Furthermore, the organoids used in this research could inspire further use in drug development and potentially in the development of personalized therapeutics.
References: Parreno V, Loubiere V, Schuettengruber B, et al. Transient loss of Polycomb components induces an epigenetic cancer fate. Nature. 2024;629(8012):688-696. doi:10.1038/s41586-024-07328-w
Singh A, Del-Valle-Anton L, de Juan Romero C, et al. Gene regulatory landscape of cerebral cortex folding. Sci Adv. 2024;10(23):eadn1640. doi:10.1126/sciadv.adn1640
Tsitkov S, Valentine K, Kozareva V, et al. Disease related changes in ATAC-seq of iPSC-derived motor neuron lines from ALS patients and controls. Nat Commun. 2024;15(1):3606. doi:10.1038/s41467-024-47758-8
Dennison TW, Edgar RD, Payne F, et al. Patient-derived organoid biobank identifies epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn’s Disease. Gut. 2024. doi:10.1136/gutjnl-2024-332043
