9/12/2023 0 Comments 10x chromium core mghHowever, studies of CAF-1 function in normal cell and tissue homeostasis have been difficult due to its requirement during DNA replication and hence its essential role in cell proliferation and organismal development 12, 15, 17, 18. Given the effect of the CAF-1 complex on chromatin accessibility in these and other cellular paradigms 14– 16, CAF-1 has been viewed as a general stabilizer of cell identity that prevents cells from adopting an open chromatin state characteristic of immature cells. Consistent with this observation, loss of CAF-1 enhances transcription factor-driven reprogramming of somatic cells to pluripotent stem cells and direct lineage conversion of pre-B cells into macrophages and that of fibroblasts into neurons. For instance, during cellular reprogramming to pluripotency, CAF-1 blocks the binding of ectopically expressed SOX2 transcription factor by maintaining a closed chromatin state at its target loci. CAF-1 is a histone chaperone that assembles nucleosomes during DNA replication and is involved in regulating heterochromatin 12, 15. We previously identified the two subunits of the CAF-1 complex, Chaf1a and Chaf1b, as key regulators of cell identity maintenance in different models of transcription factor-driven cellular reprogramming and direct lineage conversions 14. Multiple studies have linked histone chaperones to changes in cell identity, including the replication-dependent chaperone CAF-1, the replication-independent chaperones HIRA and DAXX, and the transcriptionally related chaperones FACT and SPT6 12, 13. Of the many types of molecules implicated in the control of chromatin accessibility, histone chaperones act broadly by catalyzing nucleosome assembly during DNA replication, transcription, and DNA repair 11. In this manner, altered chromatin accessibility is thought to set the stage for the activity of key TFs that in turn drive cell lineage specification. However, the mechanisms that sustain hematopoietic lineage integrity remain poorly defined.ĭuring the dynamic process of cellular differentiation, chromatin remodeling typically precedes transcriptional regulation 10. Notably, some of these TFs, such as CEBPΑ and GATA1, are, upon ectopic expression, sufficient to drive transdifferentiation into a different blood cell lineage 8, 9. In the myeloid lineage, the CCAAT/enhancer-binding protein (C/EBP) family members play major roles in commitment toward granulocytes and macrophages, while GATA1, KLF1, and GFI1B have been described to govern erythrocyte and megakaryocyte lineage commitment 7. Lineage specification during hematopoiesis is tightly controlled by transcription factors (TFs). This signifies the need to understand the molecular mechanisms that sustain the identity of stem and progenitor cells and restrict their commitment to a specific lineage during differentiation. Recent single-cell transcriptome analyses of bone marrow suggest that lineage commitment is heterogeneous and deviates from the largely cell surface marker-based, hierarchical differentiation model of hematopoiesis 1– 7. During this process, cells become progressively more restricted towards myeloid or lymphoid lineages by a stepwise transition through progenitor cell states. Hematopoiesis involves the sequential commitment of self-renewing hematopoietic stem cells to fully mature specialized blood cell types 1. Together, our findings decipher key traits of chromatin accessibility that sustain lineage integrity and point to a powerful strategy for dissecting transcriptional circuits central to cell fate commitment. We find that CAF-1 sustains lineage fidelity by controlling chromatin accessibility at specific loci, and limiting the binding of ELF1 TF at newly-accessible diverging regulatory elements. We show that CAF-1 suppression triggers rapid differentiation of myeloid stem and progenitor cells into a mixed lineage state. Here, we investigate how CAF-1 influences chromatin dynamics and TF 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. The chromatin assembly factor-1 (CAF-1) is a histone chaperone that regulates chromatin architecture by facilitating nucleosome assembly during DNA replication. Cell fate commitment is driven by dynamic changes in chromatin architecture and activity of lineage-specific transcription factors (TFs).
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