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A key role for the histone chaperone CAF-1 in sustaining cell fate

Written by Charlotte Harrison, Science Writer

Cell fate — whether a cell self-renews or differentiates — is driven by dynamic changes in the architecture of chromatin and the activity of lineage-specific transcription factors. A study in Nature Communications shows that the fate of blood stem cells is regulated by a histone chaperone called chromatin assembly factor-1 (CAF-1).

The study focused on CAF-1, which assembles nucleosomes during DNA replication, because of its known role in regulating chromatin accessibility. As a model system to study cell fate, the researchers used a controllable myeloid differentiation system with inducible gene perturbation. In this system, blood stem cells normally differentiate into mature neutrophils.

No CAF-1, no neutrophils

First, the authors suppressed CAF-1 expression in the myeloid differentiation model. Without CAF-1, cells forgot their neutrophil identity and instead turned into a mixture of cell types. In particular, loss of CAF-1 loss in the myeloid system and primary hematopoietic stem and progenitor cells activated a mixed differentiation program in which genes from different lineages, including those of neutrophils, red blood cells and megakaryocytes (cells that produce platelets) were de-repressed.

CAF-1 sustains lineage fidelity

The authors next investigated how the loss of CAF-1 triggers the mixed lineage state, using ATAC-seq and RNA-seq analyses. Overall, they showed that CAF-1 restricts the access of lineage-specific transcription factors, particularly ELF1, to chromatin. Restricted acceptability of ELF1 to chromatin then prevents spurious cell differentiation and sustains lineage fidelity. 

Future studies will involve testing the authors’ predications that CAF-1 sustains the fate of many other cell types, and delving deeper into the activity of CAF-1 in development and disease.

“Like a city, the genome has its landscape with specific landmarks,” said lead author Sihem Cheloufi in a press release. “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.”

More on these topics

Blood / Cell Fate / Chromatin / Stem Cells