UCLA researchers from the David Geffen School of Medicine have identified linker histone H1 as a critical regulator of pathologic gene expression and cellular mechanics, establishing its potential role as a therapeutic target for the treatment of fibrosis.
BACKGROUND: Heart failure affects ~6 million Americans and has a 5-year survival rate of ~50% in adults. A common feature of heart failure is impairing contraction and relaxation of the heart muscle, which leads to poor perfusion of the body, edema, extreme exhaustion and lethal cardiac arrhythmias. A major cause of cardiac muscle dysfunction is the deposition of scar tissue, known as fibrosis, which results from excessive, disorganized production of extracellular matrix, stiffening of the tissue and the activation of myofibroblasts. There are currently no treatments to prevent pathologic fibrosis in heart failure. Furthermore, other diseases like pulmonary artery hypertension, hepatic fibrosis or renal fibrosis are also driven by myofibroblast activation, which likewise leads to remodeling of the extracellular matrix and stiffening of the tissue. Previous work has shown that preventing myofibroblast activation may be a promising strategy to prevent fibrosis, but molecular targets to accomplish this goal have remained elusive. One strategy involves modulating the proteins that control gene expression by compacting the genome into chromatin: these histones, of which histone H1.0 is a member, are proteins that help organize DNA and can regulate whether genes are turned on or off.
INNOVATION: Researchers at UCLA have discovered that histone H1.0 is a molecular regulator of chromatin that modifies the mechanical behaviors of myofibroblasts, cells that synthesize connective tissue and drive fibrosis. To determine histone H1.0’s role in myofibroblast activation, researchers depleted the protein and treated the cells with Transforming Growth Factor Beta (TGF-b) to initiate a stress response common in fibrosis. They found that histone H1.0 knockdown prevented TGF-b-induced myofibroblast activation and was required for the myofibroblast mechanical behaviors associated with disease. To determine the mechanism of action, researchers then examined the role of histone H1.0 in chromatin reorganization and gene transcription: depletion of histone H1.0 was sufficient to prevent TGF-b-induced chromatin remodeling at genes necessary for fibrosis, thereby preventing their pathologic expression. Lastly, the researchers found that depletion of histone H1.0 prevents disease-associated fibrosis and cardiac dysfunction in vivo, providing important therapeutic relevance to the novel molecular mechanisms of action. The researchers are now developing molecular tools to target histone H1.0 for treatment of cardiac fibrosis in humans. In summary, UCLA researchers have identified histone H1.0 as a regulator of chromatin architecture and cellular mechanics, with a clinically relevant role in fibrosis. This ongoing work has great potential to lead to novel therapeutics for treatment of fibrotic diseases.
POTENTIAL APPLICATIONS:
ADVANTAGES:
DEVELOPMENT-TO-DATE: UCLA researchers have identified that histone H1.0 acts via chromatin reorganization to control pathologic gene expression, cellular mechanical behaviors and fibrosis in both cells and in vivo. They have shown that depletion of histone H1.0 prevents disease-associated cardiac fibrosis in a mouse model.
Related Papers (from the inventors only):
Hu, et al. "Histone H1.0 Couples Cellular Mechanical Behaviors to Chromatin Structure." Nature Cardiovascular Research, vol. 3, no. 4, Apr. 2024, https://doi.org/10.1038/s44161-024-00460-w.
KEYWORDS:
Linker histone H1, H1.0, chromatin, histones, single-cell RNA sequencing, chromatin immunoprecipitation-sequencing, nuclear deformability, chromatin condensation, fibrosis, fibrotic diseases, gene activation, heart failure, HFpEF, HFrEF, epigenetic therapy, cardiovascular disease