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The main regulator that controls the production of antibody-producing cells was identified in a research conducted by scientists from Weill Cornell Medicine. These findings offer new insights into the functioning in the immunity system. It also can help to understand how tissues form and how cancers are triggered.
The study, which was published on September. 23rd in the journal Nature Immunology It combined computational analyses combined with modern genomics and molecular biology to pinpoint a protein named Oct2 as the most important factor that determines the B-cell’s humoral immune response.
In the course of an infection or following vaccination maturing B cells form germinal centers, which are a kind form of training pop-up. The cells then undergo a mutagenesis and re-arrange their gene that encodes antibodies in order to produce better antibodies or stop trying. This process is crucial in the body’s reaction to various pathogens. However, it’s also a risk as B cell mutations that are not properly placed can lead to lymphoid cancers.
“All the cells in our bodies have mechanisms to protect themselves from getting mutated. However, B cells are actually doing their own thing and specialize in mutation, and they perform it quickly,” said co-senior author Dr. Ari Melnick, the Gebroe Family Professor of Hematology / Oncology within the Division of Hematology and Clinical Oncology and part of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
The previous studies have revealed that B cells are responsible for their germinal center maturation through altering the accessibility of the various regions of their genomes and by triggering cascades of gene expression to control and restrict their growth. But how do they coordinate all these signals?
To to answer this query, Weill Cornell Graduate School of Medical Sciences student Ashley Doane, along with colleagues from Weill Cornell Medicine and The Rockefeller University began by taking an approach using computers by mapping the entire genes that B cells experience.
“We began by making an atlas of all regulatory elements that arise and go away over the course over time” stated the researcher Dr. Melnick. Through the development of new computational techniques that the team was capable of deconvolving the changes and identify OCT2 as the molecule which was the underlying cause to the process.
However, OCT2’s distribution in germinal centers was quite similar to that of mature B-cells prior activation. By examining B cells using new molecular and genomic tools developed within the laboratory, researchers found that OCT2 is present in the B cells that are still in embryonic stage, pre-positioned within the genome regions which it later activate in the germinal center reaction. A different gene-related protein, OCA-B, causes the genomic locations identified by OCT2 to be active and transform them into “super-enhancers” that control the remainder of the B maturation regulator network.
The concept of cellular predestination and the discovery of a particular mechanism to explain it – could be the most significant discovery.
“I think it’s an important finding that could be applicable to numerous different changes between different cells,” said co-senior author Dr. Olivier Elemento, who is director of the Caryl and Israel Englander Institute for Precision Medicine and associate director of the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine at Weill Cornell Medicine.
During the embryonic process such as when one cell divides and develops into all the cells in an organism, following a sequence of branching decisions that might utilize similar mechanisms to identify super-enhancers that can be activated in the future.
The targeting of master regulators like OCT2 or OCA B, as well as their counterparts from other types of cells, could offer a new and effective method to combat cancer.
“Very often what you’ll notice is that when an individual gene is vital for maintaining the state of cancer it will be likely to be controlled by a super-enhancer” Professor. Elemento, who is also a professor of physiology as well as biophysics as well as a the professor of computational genomics and the field of computational biology in Weill Cornell Medicine. “Cancer cells rely on these for a way to keep their identities.”
Inhibiting tumor cells’ capacity to develop critical cell-type specific super-enhancers may be able to take the rug out underneath them, and shut off their entire survival strategy.
Weill Cornell Medicine
Doane, A. S., et al. (2021) OCT2 pre-positioning facilitates cell fate transition and chromatin architecture changes in humoral immunity. Nature Immunology. doi.org/10.1038/s41590-021-01025-w.