Certain chromatin “readers” are crucial for keeping track of this shape often in response to environmental signals, as the structure of chromatin, the mixture of DNA and proteins that make up chromosomes, can alter gene expression.
Some immunological illnesses, including Crohn’s disease, an inflammatory bowel disease, are related with mutations in one of these readers, called Speckled Protein 140 (SP140).
Researchers at Massachusetts General Hospital (MGH) have recently published new study in Cell that sheds light on the mechanisms behind this connection and identifies possible treatment targets.
Immune cells like macrophages, which surround and kill pathogens, eliminate dead cells, and activate the activity of other immune cells, are the only immune cells that produce SP140.
SP140 inhibits topoisomerases (TOP), which are enzymes that aid in the untangling of DNA during replication, according to research by Kate L. Jeffrey, PhD, an associate professor of medicine at Harvard Medical School and the principle investigator of immunology at Massachusetts General Hospital.
The team also discovered that in both humans and mice, SP140 depletion led to TOP activity being let loose, which in turn caused faulty gene expression and bacterial killing by macrophages that resulted in abnormalities in the intestines.
Inflammation resembling Crohn’s disease, which is still incurable despite surgical or pharmacological procedures, was treated in mice by inhibiting TOP to reverse these abnormalities.
The work broadens our understanding of epigenetics in health or the physical changes in cells’ DNA structure that affect the expression of genes in response to environmental cues. Importantly though, it revealed how dysregulation of epigenetic factors drive diseases such as Crohn’s that are rising in incidence because of the complex interplay of genes plus environment.
Kate L. Jeffrey
“Applying a combination of human genetics, proteomics, biochemistry, utilization of primary immune cells from Crohn’s disease individuals, and in vivo animal studies, our study highlights the power of examining human disease associated genetic mutations to advance mechanistic understanding of disease,” says Jeffrey.
“The work broadens our understanding of epigenetics in health or the physical changes in cells’ DNA structure that affect the expression of genes in response to environmental cues. Importantly though, it revealed how dysregulation of epigenetic factors drive diseases such as Crohn’s that are rising in incidence because of the complex interplay of genes plus environment.”
Many members of the medication family are now being evaluated in active cancer clinical trials, and several TOP inhibitors have been approved for the treatment of certain tumors. According to the most recent research, clinical trials should evaluate a drug’s ability to treat Crohn’s disease.
Additional co-authors include Hajera Amatullah, Isabella Fraschilla, Sreehaas Digumarthi, Julie Huang, Fatemeh Adiliaghdam, Gracia Bonilla, Lai Ping Wong, Marie-Eve Rivard, Claudine Beauchamp, Virginie Mercier, Philippe Goyette, Ruslan I. Sadreyev, Robert M. Anthony, and John Rioux.
The Canadian Institutes of Health Research, the Canada Foundation for Innovation, the National Institutes of Health and the MGH Research Scholar Program, supported this study. Dr. Jeffrey is a John Lawrence MGH Research Scholar 2020-2025.
