Mount Sinai researchers have made a significant scientific discovery by uncovering the biological processes through which histone deacetylases (HDACs) activate immune system cells associated with inflammatory bowel disease (IBD) and other inflammatory disorders. This breakthrough was reported in the Proceedings of the National Academy of Sciences.The latest study published in the Proceedings of the National Academy of Sciences (PNAS), suggests that the development of selective HDAC inhibitors might help in treating specific types of IBD such as ulcerative colitis and Crohn’s disease.
According to senior author Ming-Ming Zhou, PhD, from the Icahn School of Medicine at Mount Sinai, the limited understanding of the specific function of class II HDACs in different cell types has been an obstacle in the development of therapies targeting this promising drug target family. The proof-of-concept study aims to unravel the mechanisms and potential treatment options.The Mount Sinai researchers concentrated on class IIa HDACs, which have more specific functions in the body compared to class I HDACs, which have more general functions. Out of the 18 histone deacetylases found in mammals so far, HDAC4 and HDAC7, both class IIa HDACs, are notable for their involvement in controlling the growth and differentiation of Th17 cells. These cells are responsible for producing interleukin-17 (IL-17), a very inflammatory cytokine linked to various conditions such as inflammatory bowel disease (IBD), multiple sclerosis, and rheumatoid arthritis. This discovery provides crucial information that could lead to the development of safer and more effective treatments for these disorders.Multiple sclerosis, rheumatoid arthritis, and other autoimmune diseases are strongly associated with excessive activity of Th17 cells. As a result, scientists have been concentrating on ways to intervene in the activity of HDAC4/7, either through medication or genetic methods, in order to reduce inflammation caused by Th17 cells.
In a groundbreaking study, researchers at Mount Sinai have identified a previously unknown mechanism by which HDAC4 and HDAC7 work independently but in cooperation to control the differentiation and transcription of Th17 cells. Transcription is the first step in gene expression, involving the creation of RNA molecules by copying the DNA sequence, and is crucial for most biological processes.es.
The significant role of class IIa HDACs in Th17 cells and inflammatory disease has been largely unexplored until now,” says Ka Lung Cheung, PhD, Assistant Professor of Pharmacological Sciences at Icahn Mount Sinai. “Mechanistically, we’ve discovered that class IIa HDACs orchestrate both gene transcriptional activation and repression to steer the process of Th17 cell differentiation. This significant revelation deepens our comprehension of the previously ambiguous role of class IIa HDACs in biology and human disease.”
As a critical aspect of their investigation, the research team found that a potent class IIa HDAC inhibitor, the findings could have broader implications for other Th17-related conditions such as rheumatoid arthritis and psoriasis,” said lead investigator Dr. TMP269. The study’s results open up new possibilities for targeted treatments that could alleviate symptoms and improve outcomes for patients with these conditions. By focusing on the role of class IIa HDACs in the differentiation of Th17 cells, the researchers hope to develop more effective therapies that specifically target the underlying mechanisms of these diseases. Through further research and development, the goal is to create medications that can provide relief for patients suffering from Th17-related inflammatory and autoimmune diseases.”According to Dr. Zhou, our research suggests that there is potential for the development of advanced therapies that target severe inflammation in various human pathologies,” Dr. Zhou stated.
