PAH Development May Be Boosted by Epigenetic Changes, Study Reports - Pulmonary Hypertension News
PAH Development May Be Boosted by Epigenetic Changes, Study Reports - Pulmonary Hypertension News |
| PAH Development May Be Boosted by Epigenetic Changes, Study Reports - Pulmonary Hypertension News Posted: 29 May 2020 09:00 AM PDT Changes in the epigenetic profile — a collection of marks that turn genes on and off — of pulmonary arterial endothelial cells from people with pulmonary arterial hypertension (PAH) may contribute to disease development, a study suggests. The study, "Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension," was published in the journal Nature Communications. PAH is considered a multifactorial disease, meaning its cause is not only associated with genetic DNA variations but also with environmental cues that influence the cells' epigenetic profile, which are external modifications to DNA that act as switches to turn genes on and off without changing the actual DNA sequence. In fact, most cases of idiopathic PAH (IPAH) are not linked to a genetic mutation. Reports suggest that only about 15% of PAH patients have familial IPAH, and of those, 70% carry a mutation in the BMPR2 gene. "Most PAH cases aren't caused by any known mutation, and there was a hypothesis that the disease is caused by epigenetic changes," Judith Zaugg, a group leader at EMBL in Germany and the study's co-senior author, said in an EMBL news story. To study how epigenetic alterations affected the course of PAH, researchers analyzed the epigenetic profile of pulmonary arterial endothelial cells (PAECs) from PAH patients and how it differed from that of healthy cells. PAECs compose the lining of lung blood vessels and play an important role in PAH. The team collected PAECs from the lungs of 19 patients with IPAH and hereditary PAH who had received a transplant, as well as from healthy donor lungs. Epigenetic analysis revealed that genomic regions called enhancers were completely remodeled in PAECs from PAH patients compared with healthy controls. A total of 11,701 sites (loci) were found to carry different epigenetic marks. But the level of gene activity — called gene expression — remained unchanged. "The surprising thing was that we were expecting strong differences in the gene expression levels, but couldn't find anything. Usually, in these types of disease studies, the differences in gene expression are huge," said Armando Reyes Palomares, the study's first author. Enhancers are regulatory DNA sequences found in a region of the genome that do not provide instructions for making proteins but work as switches that regulate gene expression. By matching enhancers to genes, the researchers found that modified enhancers were strongly associated with the proliferation and migration of endothelial cells. Next, the team investigated whether transcription factors (TFs), proteins that also regulate gene expression, were involved in these differences between PAH and healthy cells. They found that 318 TFs acted differently between diseased and healthy cells. To better understand how these TFs were influencing genes in PAH, the researchers developed a computational model called cell-type specific gene regulatory network. The analysis revealed that 1,880 genes regulated by TFs acted in different ways in PAH compared with controls. "The results are disappointing as far as finding potential drug targets is concerned," Zaugg said. "It seems that, in PAH patients, the cell is in a completely different state. It's not just one single switch that you can turn back." Nonetheless, the findings contribute to a better understanding of the mechanisms associated with PAH. "It shows that there is much more information to be found in the chromatin [epigenetic] states of a cell, rather than only looking at gene expression levels," Zaugg said. The team believes that epigenetic changes may prime endothelial cells "to respond in an aberrant way in PAH patients, which could then lead to abnormal growth or differentiation" and the obstruction of arteries. This new method of analysis will also help to find new links between epigenetic alterations and molecular mechanisms in diseases, they said. "We present a powerful framework for integrating multiple omics data in enhancer-mediated gene networks that allow the identification of genes driving disease-specific pathways and give insights to disease mechanisms," they concluded.  Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York. × Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York. Latest Posts  |
| I'm Celebrating a Year with You - Pulmonary Hypertension News Posted: 11 May 2020 12:00 AM PDT "There is ebb and flow. Leaving and coming. Flight and fall. Sing and silent. Reaching and reached." – Ally Condie I am unfamiliar with the author of that quote and her thoughts behind it. But as I prepared to write my one-year anniversary column, it grabbed my attention. The words describe well how I have approached awareness and advocacy throughout my son's pulmonary hypertension (PH) battle and during his post-transplant life. As Condie's words describe so eloquently, I have found during our family's PH journey that my participation in these goals has ebbed and flowed, depending on my need and ability. Experience has taught me that this changing of the tides is a normal and healthy approach to dealing with a rare and life-threatening disease. After my son Cullen was diagnosed with PH, I spent most of the first year educating myself about the disease and developing my advocacy skills. A wonderful group of PH moms welcomed us into their circle, and we supported one another by email and in a Facebook group called "Families of Children with Pulmonary Hypertension." As a newbie, I asked a lot of questions and took notes based on the experiences of others. I also silently listened when members discussed fundraisers, conferences, and other ways they were raising their voices about PH. This all made a big impression on me, but I was not yet ready to jump into spreading awareness. Eventually, my son's quality of life improved, and I was well on my way to earning what felt like an honorary medical degree. My family had adapted to a new normal, and despite the predator that had invaded our lives, we began to share happy moments again. It took all this to happen before I truly felt comfortable discussing PH with others and explaining the desperate need for awareness. I also noticed that the support group had transitioned into an extended family of sorts. With them, I felt most comfortable voicing concerns, asking questions, sharing good and bad days, listening instead of speaking, or sometimes even disappearing for a while. During periods of extraordinary stability or overwhelming decline, I occasionally needed a mental health break from PH. I would take short breaks from the group so I could free myself from constant PH thoughts. This helped me enjoy the good times, and not snap like a twig during the bad. My PHamily understood and was always there for me when I returned or checked in on me if I was away too long. They were there for me during the final fall, when my son was out of treatment options and listed for a transplant. And they rejoiced with me after his successful surgery. A few months post-transplant, Cullen and I took part in the "Race Against PH 5K," but after that, we took a sabbatical from awareness and advocacy during that first year of recovery. He no longer had PH, but his new heart and lungs came with a lot of responsibility and much to be learned. We had to take the time to adjust to this new normal. As time passed and Cullen was doing well, I started offering more attention again to PH awareness. When he approached his fifth transplant anniversary, I considered how much stories like his had provided us with hope and support in the past. While searching for a way to pay it forward, former Pulmonary Hypertension News Forums moderator and columnist Kathleen Sheffer mentioned that she was leaving her position to focus on her photography business. I jumped at the opportunity to become a moderator, and recently celebrated my first anniversary with Pulmonary Hypertension News. I have tried to make my column, "Life As a Caregiver," an open and honest journey forged by the struggles and strengths that my son and the rest of my family have endured through the years. His PH and transplant journey has not been easy, but it has not lacked hope, and that is what I try to inspire in others. As a forums moderator, I offer the understanding that we are all in different stages of PH awareness and advocacy. I appreciate the members who actively share and ask questions, but understand those who would rather quietly read and reflect. Sing or be silent, we welcome all! New topics are offered weekly, and we frequently revisit past ones so that no matter what phase of PH you are experiencing, you have material to read that might help you. If you have a question but feel uncomfortable asking it, send a private message to me or co-moderators Jen Cueva and Brittany Foster. We will happily ask it for you and make your forums experience a positive one. Thank you, column readers and forum members, for providing me with the understanding and support that I have tried to provide to you. I look forward to another inspiring year. *** Note: Pulmonary Hypertension News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Pulmonary Hypertension News or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to pulmonary hypertension.  |
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