HDAC4

In a scientific breakthrough, researchers have revealed the biological mechanisms by which a family of proteins known as histone deacetylases (HDACs) activate immune system cells linked to inflammatory bowel disease (IBD) and other inflammatory diseases. In a scientific breakthrough, Mount Sinai researchers have revealed the biological mechanisms by which a family of proteins known as histone deacetylases (HDACs) activate immune system cells linked to inflammatory bowel disease (IBD) and other inflammatory diseases. This discovery, reported in Proceedings of the National Academy of Sciences (PNAS), could potentially lead to the development of selective HDAC inhibitors designed to treat types of IBD such as ulcerative colitis and Crohn's disease. "Our understanding of the specific function of class II HDACs in different cell types has been limited, impeding development of therapies targeting this promising drug target family," says senior author Ming-Ming Zhou, PhD, Dr. Harold and Golden Lamport Professor in Physiology and Biophysics and Chair of the Department of Pharmacological Sciences at the Icahn School of Medicine at Mount Sinai. "Through our proof-of-concept study, we're unraveling the mechanisms of class II HDACs, providing essential knowledge to explore their therapeutic potential for safer and more effective disease treatments." The Mount Sinai team focused specifically on class IIa HDACs, which exhibit more tissue-specific functions than class I HDACs, which act more broadly. Among the 18 histone deacetylases discovered to date in mammals, HDAC4 and HDAC7 -- both class IIa HDACs -- stand out for their roles in regulating the development and differentiation of Th17 cells. These cells are known for producing interleukin-17 (IL-17), a highly inflammatory cytokine associated with a spectrum of disorders, including IBD, multiple sclerosis, and rheumatoid arthritis. Given the strong correlation between excessive Th17 cell activity and human disease, scientists have focused on pharmacological or genetic interventions targeting HDAC4/7 to mitigate Th17 cell-mediated inflammation. In their groundbreaking study, the Mount Sinai researchers delineated a previously unrecognized mechanism by which HDAC4 and HDAC7 operate independently yet cooperatively to govern Th17 cell differentiation and transcription. Transcription is the initial step of gene expression involving copying of the DNA sequence to generate RNA molecules; it is crucial for most biological processes. "The role of class IIa HDACs in Th17 cells and inflammatory disease has been largely unexplored until now," notes lead author 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, TMP269, influenced the differentiation of Th17 cells in a mouse model of ulcerative colitis. This pivotal discovery underscores the potential of pharmacological inhibition of class IIa HDACs as a promising therapeutic approach for addressing Th17-related inflammatory and autoimmune diseases, the study reported. Expanding on this foundation of knowledge, researchers in the Zhou Lab and the Cheung Lab at Mount Sinai plan to concentrate on refining class IIa HDAC inhibitors with better efficacies for treating various types of Th17-mediated diseases. "While our study primarily examined inflammatory bowel disease, specifically colitis," says Dr. Zhou, "we believe our findings pave the way for extensive research into advanced therapies targeting severe inflammation in various other pathologies within the human body."

Researchers found that, in neurons that produced the neuropeptide NMS, the interaction between molecules SIK3 and HDAC4 has a critical role in sleep regulation through both the length of the circadian period and sleep homoeostasis. Given the similarities among different mammals, new information about how the circadian system works in mice could lead to new treatments for sleep and circadian rhythm disorders in humans. Most living creatures exhibit a circadian rhythm, an internal clock that repeats around every 24 hours. Now, researchers from Japan have found new details about the molecular processes that govern sleep/wake rhythms in mice. In a recently published study, researchers from the University of Tsukuba have revealed that a key molecule involved in sleep homeostasis (called SIK3 or salt-inducible kinase 3) also plays a critical role in circadian behavior. Animals are able to adapt to the 24-hour cycle of light and dark in terms of both behavior and physiology via changes in the suprachiasmatic nucleus (SCN), which is the brain's master clock that synchronizes the various rhythms in the body. However, the biological activities within the SCN that induce time-specific wakefulness have not been fully characterized; the research team aimed to address this. "Most animals show a peak in activity at a specific point in the circadian cycle," explains lead author of the study Professor Masashi Yanagisawa. "Because the SCN has been found to regulate sleep and wakefulness at certain times of the day, we wanted to investigate the distinct neurons that control this process." To do this, the research team genetically manipulated levels of SIK3 in specific neuron groups in the SCN of mice. Then, they examined sleep and circadian behaviors in the mice, such as when and for how long the mice exhibited activity with respect to the light-dark cycle. "We found that SIK3 in the SCN can influence circadian cycle length and the timing of peak arousal activity, without changing the daily sleep amount," says Professor Yanagisawa. The research team previously reported that SIK3 interacts with LKB1 (an upstream molecule of SIK3) and HDAC4 (an important target of SIK3) in glutamatergic neurons to regulate the amount and depth of sleep. Now, they have found that the SIK3-HDAC4 pathway modulates the length of the circadian period through NMS-producing neurons, and contributes to the sleep/wake rhythm. The length of the behavioral period and the timing of peak activity are important components of the circadian rhythm. Given the similarities between the circadian systems of different mammals, new information about how this system works in mice could lead to new treatments for sleep and circadian rhythm disorders in humans. This work was supported by the World Premier International Research Center Initiative (WPI) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (KAKENHI), Japan Science and Technology Agency (JST) Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), JSPS DC2 grant, University of Tsukuba Basic Research Support Program Type A, and Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program).

sCFH is an engineered and improved version of complement factor H. Credit: Deposition authors: Jaakola, V-P, Jokiranta, TS, Goldman, A. Visualisation author: User: Astrojan/ commons.wikimedia.org Fortress Biotech subsidiary Aevitas Therapeutics has signed an asset purchase deal to sell the proprietary rights to its short-form human complement factor H (sCFH) asset to 4D Molecular Therapeutics for $140m in cash. sCFH is an engineered and improved version of complement factor H (CFH) that can fit into adeno-associated virus (AAV) vectors with solid expression and applications confirmed in cultured human cells in vitro, in addition to various preclinical animal models in vivo. Recommended Reports Reports Bromodomain Containing Protein 4 (Protein HUNK1 or BRD4) Drugs in Development by Therapy Areas an... GlobalData Reports Histone Deacetylase 4 (Histone Deacetylase A or HDAC4 or EC 3.5.1.98) Development by Therapy Area... GlobalData View all Reinstating CFH function by employing the sCFH protein could restore normal complement regulation and minimise retinal injury that manifests as progressive geographic atrophy (GA). Aevitas will receive the payment as potential late-stage development, regulatory and sales milestones. The firm will also receive single-digit royalties on net sales. 4DMT will be responsible for licence payments to the University of Pennsylvania, where the Perelman School of Medicine’s pharmacology professor, Dr Wenchao Song, jointly invented and developed the sCFH technology. Fortress chairman, president and CEO and Aevitas executive chairman Lindsay A Rosenwald stated: “This agreement with 4DMT allows Fortress to focus on acquiring and developing clinical-stage treatments, while potentially expediting the development and commercialisation of this preclinical sCFH technology. “Partnering with 4DMT further validates the Fortress business model of identifying and developing promising treatments for patients, while pursuing opportunities that potentially maximise shareholder value. “We look forward to 4DMT using their vector platform to continue the development of the sCFH asset to potentially treat geographic atrophy (GA) and other diseases.”