Understanding the molecular mechanisms that determine and maintain the identity of more than 200 cell types in the human body is believed to be one of the most fundamental in cellular and molecular biology, with important implications for the future. treatment of human diseases. At the heart of the cell fate process are stem cells located in every body tissue.
When stem cells divide, they have the remarkable ability to choose to renew themselves – that is, make a copy of themselves – or to mature into defined lineages. A better understanding of how a specific lineage identity is maintained each time a stem cell divides can be achieved thanks to the work of a team led by biochemists at the University of California, Riverside.
Research by Sihem Cheloufi and Jernej Murnboth assistant professors in Department of Biochemistry, showing how a protein complex, called chromatin assembly factor-1, or CAF-1, controls genome organization to maintain lineage fidelity. The report appeared today in Nature Communications.
Each time a cell divides, it must make a copy of its genome – its DNA sequence and the way that DNA is packed with the proteins it makes up. chromatin. Chromatin is organized into either open and accessible genomic sites or more densely packed and less accessible (or closed) genomic sites.
“The identity of different cells is mainly based on more open genomic sites because only genes located in those regions are capable of being expressed and transformed into proteins,” Cheloufi explain.
She adds that in order to maintain cell identity during cell division, the sites of open and closed chromatin, or “chromatin organization,” must be faithfully transferred into the transcript. novel of the genome, the task was mainly assigned to CAF-1.
Sihem Cheloufi (left) and Jernej Murn are assistant professors of biochemistry at UC Riverside. Image credit: UCR / Stan Lim
“To help CAF-1 protect the correct chromatin organization during cell division, a variety of transcription factors are attracted to open regions in a DNA sequence-specific manner to act as bookmarks and recruits transcription machinery to edit clan-specific genes, ensuring their expression,” she said. “We wondered about how CAF-1 is needed to maintain organization cell-specific chromatin during cell division.”
The authors studied the modeling of immature blood cells that can either self-renew or transform into neutrophils, which are undivided cells that serve as the body’s first line of defense against pathogens. sick. Interestingly, they found that CAF-1 is required not only to maintain the self-renewal capacity of these immature blood cells, but also to preserve their lineage identity. Even a moderate decrease in CAF-1 levels causes cells to forget their identity and adopt a mixed lineage stage.
“CAF-1-deficient neutrophil stem cells become more plastic, co-expressing genes from different lineages, including red blood cells and platelets,” said Cheloufi. “This is very intriguing from a developmental biology point of view.”
At the molecular level, the team found that CAF-1 often keeps specific genomic sites tightly packed and inaccessible to specific transcription factors, particularly one called is ELF1.
“By looking at chromatin organization, we found a wide range of gene sites that expand and attract ELF1 due to loss of CAF-1,” Whisper speak. “Our study further points to an important role for ELF1 in determining the fate of several blood cell lines.”
The UCR researchers used immature blood cells derived from mouse bone marrow and engineered to grow in tissue culture. They validated their findings in vivo using a mouse model in collaboration with Andrew Volk, a hematologist at Cincinnati Children’s Hospital Medical Center and a co-author of the study.
Next, Cheloufi and her colleagues wanted to understand the mechanism by which CAF-1 maintains chromatin state at specific sites, and whether this process behaves differently on different cell types.
“Like a city, the genome has a landscape with specific landmarks,” says Cheloufi. “It would be interesting to know exactly how CAF-1 and other molecules maintain the genome ‘horizontal’. Solving this problem could also help us understand how the fate of cells works in a predictable way. Given the fundamental role of CAF-1 in genome packaging during DNA replication, we expected it to act as a general gatekeeper of cellular identity. In principle, this would apply to all cells that divide across multiple tissues, such as cells in the intestines, skin, bone marrow, and even the brain. ”
The source: UC Riverside
