When stem cells divide, they have the remarkable ability to choose to self-renew or mature into defined lineages. How a specific lineage identity is maintained every time a stem cell divides is now better understood thanks to new research that shows how the histone chaperone chromatin assembly factor-1 (CAF-1) controls genome organization to maintain lineage fidelity.

The study investigated how CAF-1 influences chromatin dynamics and transcription factor activity during lineage differentiation. Accumulating evidence supports a substantial role of CAF-1 in cell fate maintenance, but the mechanisms by which CAF-1 restricts lineage choice remain poorly understood.

This work is published in Nature Communications, in the paper, “Regulation of chromatin accessibility by the histone chaperone CAF-1 sustains lineage fidelity.”

“Identities of different cells rely heavily on the genome sites that are more open because only genes located in those regions can potentially become expressed and turned into proteins,” said Sihem Cheloufi, PhD, assistant professor in biochemistry at the University of California at Riverside.

Cheloufi added that to maintain cell identity during cell division, the locations of open and closed chromatin, or “chromatin organization,” must be faithfully passed onto the new replica of the genome, a task largely entrusted to CAF-1.

“To help CAF-1 secure correct chromatin organization during cell division, a host of transcription factors are attracted to open regions in a DNA sequence-specific manner to serve as bookmarks and recruit transcription machinery to correct lineage-specific genes, ensuring their expression,” she said. “We wondered about the extent to which CAF-1 is required to maintain cell-specific chromatin organization during cell division.”

The authors studied immature blood cells that can either self-renew or turn into neutrophils—nondividing immune cells. They found CAF-1 to be essential not only for maintaining the self-renewal of these immature blood cells, but for preserving their lineage identity. Even a moderate reduction of CAF-1 levels caused the cells to forget their identity and adopt a mixed lineage stage. More specifically, the authors showed that CAF-1 suppression “triggers rapid differentiation of myeloid stem and progenitor cells into a mixed lineage state.”

“Neutrophil stem cells missing CAF-1 become more plastic, co-expressing genes from different lineages, including those of red blood cells and platelets,” Cheloufi said. “This is very intriguing from a developmental biology perspective.”

At the molecular level, the team found that CAF-1 normally keeps specific genomic sites compacted and inaccessible to specific transcription factors, especially ELF1. The authors write that CAF-1 sustains lineage fidelity by controlling chromatin accessibility at specific loci, and limiting the binding of ELF1 transcription factor at newly-accessible diverging regulatory elements.

“By looking at chromatin organization, we found a whole slew of genomic sites that are aberrantly open and attract ELF1 as a result of CAF-1 loss,” said Jernej Murn, PhD, assistant professor in the department of biochemistry at the University of California, Riverside. “Our study further points to a key role of ELF1 in defining the fate of several blood cell lineages.”

The researchers used immature blood cells derived from mouse bone marrow and engineered for growth in tissue culture. They validated their findings in vivo using a mouse model.

Next, Cheloufi and her colleagues would like to understand the mechanism by which CAF-1 preserves the chromatin state at specific sites and whether this process works differently across different cell types.

“Like a city, the genome has its landscape with specific landmarks,” Cheloufi said. “It would be interesting to know how precisely CAF-1 and other molecules sustain the genome’s ‘skyline.’ Solving this problem could also help us understand how the fate of cells could be manipulated in a predictive manner. Given the fundamental role of CAF-1 in packaging the genome during DNA replication, we expect it to act as a general gatekeeper of cellular identity. This would in principle apply to all dividing cells across numerous tissues, such as cells of the intestine, skin, bone marrow, and even the brain.”

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