New insights into mechanisms of Crohn’s disease point to potential therapeutic target

Cell (2022). DOI: 10.1016/j.cell.2022.06.048″ width=”800″ height=”530″/>

Credit: Hajera Amatullah et al, Cell (2022). DOI: 10.1016/j.cell.2022.06.048

The structure of chromatin – the mix of DNA and proteins that make up chromosomes – can affect gene expression, and certain chromatin “readers” are important for monitoring this structure often in response to environmental cues.

Mutations in one of these drives, called Speckled Protein 140 (SP140), are associated with an increased risk of certain immune diseases, including Crohn’s disease, a type of inflammatory bowel disease.

New research by researchers at Massachusetts General Hospital (MGH) and published in Cell provides insight into the mechanisms behind this link, pointing to potential therapeutic targets.

The expression of SP140 is only limited to immune cells such as macrophages, which surround and kill microorganisms, eliminate dead cells and stimulate the action of other immune cells.

Protein analyzes by Kate L. Jeffrey, Ph.D., senior researcher in immunology at the MGH and associate professor of medicine at Harvard Medical School, and her colleagues revealed that SP140 represses topoisomerases (TOPs), which are enzymes that help untangle DNA during replication.

The team also found that in humans and mice, loss of SP140 led to raging TOP activity, ultimately leading to defective gene expression and bacterial killing by macrophages that caused intestinal abnormalities. TOP inhibition rescued these defects in mice with inflammation characteristic of Crohn’s disease, a disease that remains incurable by surgical or therapeutic interventions.

“By applying a combination of human genetics, proteomics, biochemistry, the use of primary immune cells from individuals with Crohn’s disease, and in vivo animal studies, our study highlights the power of examination of genetic mutations associated with human disease to advance the mechanistic understanding of disease,” says Jeffrey.

“The work expands our understanding of epigenetics in health – or the physical changes in the DNA structure of cells that affect gene expression in response to environmental cues. Most importantly, he revealed how the dysregulation of epigenetic factors causes diseases such as Crohn’s disease to increase. incidence due to the complex interplay of genes and environment.”

Several TOP inhibitors are approved for the treatment of certain cancers, and many drugs in the class are being tested in ongoing cancer clinical trials. These latest findings indicate that clinical trials should also test their effectiveness against 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.

Epigenetic enzyme is lacking in some patients with Crohn’s disease

More information:
Hajera Amatullah et al, loss of function of epigenetic drive SP140 leads to Crohn’s disease due to uncontrolled macrophage topoisomerases, Cell (2022). DOI: 10.1016/j.cell.2022.06.048

Journal information:

Provided by Massachusetts General Hospital

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