Epigenetics in Disease Modulation

Epigenetics and the Control of Gene Expression ‼️ Epigenetics is the study of how environmental factors and behaviors can cause changes in gene expression without changing the DNA sequence. These changes can be inherited by future generations, and they can have a significant impact on health and disease. One of the most well-studied epigenetic mechanisms is DNA methylation. DNA methylation is the addition of a methyl group (CH3) to a cytosine nucleotide in DNA. This modification can silence a gene by preventing it from being transcribed into RNA. Another important epigenetic mechanism is histone modification. Histones are proteins that DNA is wrapped around. Histone modifications can change the way that DNA is packaged, which can affect gene expression. For example, histone acetylation makes DNA more accessible to transcription factors, which can increase gene expression. Epigenetic changes can also be mediated by non-coding RNAs. Non-coding RNAs are RNA molecules that do not encode proteins. They can regulate gene expression by binding to DNA or RNA, or by interfering with the translation of mRNA into proteins. The study of epigenetics is still in its early stages, but it has the potential to revolutionize our understanding of how genes work and how they influence health and disease. Epigenetic changes can be influenced by environmental factors such as diet, stress, and exposure to toxins. This means that we may be able to prevent or reverse epigenetic changes that contribute to disease by making changes to our lifestyle. Here are some examples of how epigenetics can affect gene expression: Diet: A diet rich in folate and choline has been shown to increase DNA methylation in genes that are involved in regulating cell growth and differentiation. This may help to protect against cancer. Stress: Chronic stress can lead to changes in histone modifications that can silence genes that are involved in the stress response. This may make people more susceptible to stress-related diseases such as anxiety and depression. Exposure to toxins: Exposure to environmental toxins such as pollutants and pesticides can lead to changes in DNA methylation that can increase the risk of cancer. Epigenetic changes are reversible, and there are a number of potential therapeutic strategies that are being developed to target epigenetic mechanisms. These strategies include: Dietary interventions: Changing the diet to include more foods that promote healthy epigenetic patterns may help to prevent or reverse epigenetic changes that contribute to disease. Exercise: Exercise has been shown to have a positive impact on epigenetic patterns, and it may be a way to prevent or reverse epigenetic changes that contribute to disease. Drug therapy: There are a number of drugs that are being developed that target epigenetic mechanisms. These drugs may be used to treat diseases such as cancer, obesity, and neurodegenerative disorders.

Liver fibrosis is a complex, progressive liver scarring condition affecting millions globally with very few treatment options. Driven by this unmet need, we have been collaborating with Dr Gary Peltz at Stanford University School of Medicine to explore how our Google DeepMind Google Research AI co-scientist might assist in uncovering novel therapeutic avenues for this challenging disease. Really excited to share comprehensive experimental validation results, led by Yuan Guan, Jakkapong Inchai, Zhuoqing Fang from Dr. Peltz’s lab, demonstrating our co-scientist's efficacy in uncovering promising targets and drug repurposing candidates for this disease. We specifically tasked the AI co-scientist with the challenge: "Propose novel hypotheses about specific epigenetic changes contributing to myofibroblast formation in liver fibrosis and indicate what drugs should we test as new treatments... Novel experiments performed in hepatic organoids are preferred". The AI co-scientist proposed that epigenetic alterations, particularly histone deacetylation and changes in DNA methylation, are crucial in driving fibrosis. It then suggested specific drug classes to test this, including HDAC inhibitors (like Vorinostat), DNMT inhibitors, and Bromodomain (BRD4) inhibitors. In subsequent experiments using a high-throughput micro-human hepatic organoid (microHO) platform pioneered by Dr Peltz’s lab, we found that: 1. Vorinostat (an FDA-approved HDAC inhibitor) and BRD4 inhibitors indeed showed potent anti-fibrotic effects in our human liver organoid models, without causing toxicity at effective concentrations. 2. Further supporting the co-scientist's line of reasoning, Vorinostat was observed to significantly reduce TGFβ-induced chromatin structural changes (by 91%) and also promoted the regeneration of liver parenchymal cells. While the DNMT1 inhibitor suggested by the system did not prove effective, the success with HDAC and BRD4 inhibitors highlights the AI co-scientist's potential to act as a valuable partner for scientists tackling complex diseases. By helping formulate detailed, testable hypotheses rooted in scientific literature, the co-scientist can meaningfully assist in navigating the complexities of disease and rapidly accelerate the path towards new cures. Notably, this work was done with an older version of the system.  We have made considerable progress building on the latest Gemini 2.5 models and look forward to sharing more progress soon. Huge thanks to our incredible collaborators at Stanford and with amazing teammates at Google Research Google DeepMind Google Cloud: Tao Tu, Juro Gottweis Yunhan Xu Keran Rong Artiom Myaskovsky Alexander Daryin Annalisa Pawlosky Kavita Kulkarni Anil Palepu Wei-Hung Weng Alan Karthikesalingam MD PhD Preprint link - https://lnkd.in/eADZ8tJd AI co-scientist blog - https://lnkd.in/gEDeaRfu

Epigenetic underpinnings of tumor-immune dynamics in prostate cancer immune suppression. https://lnkd.in/ehvPuVdD "Prostate cancer (PC) is immunosuppressive and refractory to immunotherapy. Infiltration of myeloid-derived suppressor cells (MDSCs) and senescent-like neutrophils and T cell exhaustion are observed in the tumor microenvironment (TME) following androgen receptor (AR) antagonism with antiandrogens or androgen ablation. De novo post-translational acetylation of the AR, HOXB13, and H2A at K609, K13, and K130, respectively, and phosphorylation of H4 at Y88 have emerged as key epigenetic modifications associated with castration-resistant PC (CRPC). The resulting chromatin changes are integrated into cellular processes via phosphorylation of the AR, ACK1, ATPF1A, and SREBP1 at Y267, Y284, Y243/Y246, and Y673/Y951, respectively. In this review, we discuss how these de novo epigenetic alterations drive resistance and how efforts aimed at targeting these regulators may overcome immune suppression observed in PC." Interesting review exploring epigenetic mechanisms of prostate cancer immune suppression, by Duminduni Yashoda and Nupam Mahajan Lab

🟥 Epigenome Editing with CRISPR-Based DNA Methylation and Demethylation for Reversible Gene Regulation CRISPR technology has expanded from genome editing to the field of epigenome editing, providing a way to regulate gene expression without changing the underlying DNA sequence. By using CRISPR-based DNA methylation and demethylation tools, scientists can modulate gene activity in a reversible manner, making it a promising approach for treating cancer, neurological diseases, and metabolic diseases. Unlike traditional gene editing, epigenetic modifications are dynamic and do not introduce permanent mutations, providing a safer alternative for precision medicine. Adding DNA methylation to gene promoters often silences gene expression, making it a useful tool for inhibiting disease-causing genes. By fusing catalytically inactive dCas9 to DNA methyltransferases (DNMT3A or DNMT3B), researchers can precisely target and methylate specific genomic sites, resulting in stable but reversible gene inhibition. This approach is particularly valuable in cancer therapy, where oncogene silencing can help suppress uncontrolled cell growth. Conversely, CRISPR-based DNA demethylation can activate genes by removing methylation marks at target sites. This is achieved by fusing dCas9 to a demethylase such as TET1, which can reactivate silenced tumor suppressors, developmental genes, or metabolic regulators. This approach has the potential to treat genetic diseases caused by epigenetic silencing, such as Fragile X syndrome or imprinting diseases. One of the main advantages of epigenome editing is its reversibility and dynamic nature, allowing for fine-tuned control of gene expression without permanent genome modification. This makes it a valuable tool for studying gene function, cell reprogramming, and disease modeling. In addition, epigenome editing can reduce off-target effects and long-term risks compared to traditional CRISPR gene editing methods. With advances in AI-driven guide RNA design, improved epigenetic effector fusion proteins, and nanoparticle-based delivery methods, CRISPR epigenome editing is emerging as a powerful tool for precision medicine and regenerative therapies. As research progresses, this technology may pave the way for personalized, reversible gene therapy for complex diseases. References [1] Jacob Goell et al., Trends in Biotechnology 2021 (DOI: 10.1016/j.tibtech.2020.10.012) [2] Paul Enriquez, Yale Journal of Biology and Medicine 2016 (https://lnkd.in/e2M7pq5C) #CRISPR #Epigenetics #GeneTherapy #PrecisionMedicine #GenomeEditing #EpigenomeEditing #BiotechInnovation #SyntheticBiology #CancerResearch #RegenerativeMedicine #BiomedicalBreakthroughs #CSTEAMBiotech

🧬 Epigenetics: The Invisible Driver of Cancer Progression While mutations often take the spotlight, epigenetic alterations play a critical and often reversible role in cancer biology. This graphic breaks down three key epigenetic mechanisms: 1️⃣ Chromatin remodeling – Loss of repressive marks (e.g., H4K20me3) and gain of activating marks (e.g., H4K16Ac) boosts oncogene transcription. 2️⃣ DNA methylation – Hypomethylation leads to inappropriate gene expression and genomic instability. 3️⃣ Non-coding RNAs – Dysregulation of lncRNAs and miRNAs can disrupt mRNA translation and tumor suppressor gene control. 🧪 These pathways are being actively pursued in the clinic with HDAC inhibitors, DNMT inhibitors, and epigenetic-targeting antisense oligos. As we move toward multi-omic profiling and combination immuno-epigenetic therapies, understanding these molecular layers is critical. Working on epigenetic biomarkers or therapies? Let’s exchange insights. #Epigenetics #CancerBiology #OncologyPipeline #ChromatinRemodeling #DNAmethylation #NonCodingRNA #TargetedTherapy #PrecisionOncology #TranslationalResearch #BiotechInnovation *Made in BioRender for Educational Purposes*

#RA and #Epigenetic_Inhibitors RA is a chronic autoimmune disease where the body attacks its own joints. Current treatments can help, but there's no cure. Modifying histone acetylation can influence gene expression and calm down overactive immune cells. This involves enzymes like HATs and HDACs. Study screened 25 compounds targeting these enzymes. They found that certain inhibitors, especially those affecting HDAC6, showed promise in reducing inflammation. #KeyFindings: > #Targeted_Effects: Some compounds showed strong effects on specific cell types, like monocytes and NK cells. > #Concentration_matters: The impact of these drugs varied based on their concentration. > #Shared_Pathways: Some inhibitors, like Ricolinostat, showed effects similar to existing RA drugs. Further studies and clinical trials are needed to see if these treatments are safe and effective. https://lnkd.in/emg_qyn6 https://lnkd.in/eYw3pvZQ #TheScienceCircuit #TranslationalResearch #RheumatoidArthritis #Epigenetics #AutoimmuneDisease #MultiOmics

*The placenta and cancer—one sustains life, the other threatens it. Yet beneath the surface, they share a surprising set of biological behaviours*. The placenta, though temporary, exhibits some of the most aggressive physiological behaviors seen in human biology—yet it does so in a precisely regulated and non-pathological manner. Interestingly, many of these behaviors mimic the hallmarks of cancer. Understanding how the placenta turns these tumor-like traits on and off at specific times could help us decode how to suppress similar pathways in cancer. Here’s where the overlap becomes fascinating:     Angiogenesis Just like tumors, the placenta induces new blood vessel formation (via VEGF and other pathways) to support the fetus. But again, it does so with spatial and temporal precision.     Invasive Growth Trophoblast cells of the placenta invade the maternal endometrium to establish nutrient exchange. This invasion is highly controlled and ends once proper placental function is established—unlike cancer, which exhibits unchecked invasion of tissues.     Immune Evasion The placenta evades the maternal immune system to avoid rejection of the fetus (which is genetically half-foreign). It uses mechanisms like HLA-G expression, Treg cell recruitment, and cytokine modulation—mechanisms also exploited by tumors to avoid immune surveillance.     Epigenetic Plasticity Both trophoblast and cancer cells demonstrate epigenetic reprogramming, changes in DNA methylation, and histone modifications—critical for regulating genes linked to invasion, growth, and immune response.  The knowledge about the similarities could offer biomimetic models to study tumor progression and immune tolerance. Most importantly, it reinforces the idea that cancer is not always a foreign behavior—but a distorted version of biological processes meant to support life.