The Histone Chaperone CAF-1 Sustains Myeloid Lineage Identity

Abstract

During hematopoiesis, stem and progenitor cells become progressively restricted in their differentiation potential. This process is driven by lineage-specific transcription factors and is accompanied by dynamic changes in chromatin structure. The chromatin assembly factor complex CAF-1 is a key regulator of cellular plasticity in various cell lineages in different organisms. However, whether CAF-1 sustains lineage identity during normal homeostasis is unclear. To address this question, we investigated the role of CAF-1 in myeloid progenitor cells. CAF-1 suppression in myeloid progenitors triggered their rapid commitment but incomplete differentiation toward granulocyte, megakaryocyte, and erythrocyte lineages, resulting in a mixed cellular state. Through comparison with a canonical paradigm of directed terminal myeloid differentiation, we define changes in chromatin accessibility that underlie a unique transcriptome of the aberrantly matured CAF-1 deficient cells. We further identify C/EBPα and ELF1 as key transcription factors whose control of myeloid lineage commitment is kept in check by CAF-1. These findings shed new light on molecular underpinnings of hematopoiesis and suggest that manipulation of chromatin accessibility through modulating CAF-1 levels may provide a powerful strategy for controlled differentiation of blood cells.

Cell Fate Decisions in the Wake of Histone H3 Deposition

“…In this setting, CAF-1, in addition to its nucleosome assembly function, is proposed to cooperate with DNA and histone modifying enzymes by binding directly to histone deacetylase and histone demethylases to ensure heritable silencing of the CD4 gene. More recently, single cell profiling demonstrates that CAF-1 loss in myeloid progenitor cells triggers their partial differentiation leading to a mixed cellular state (Preprint, Guo et al, 2020). Interestingly, in comparison to normal myeloid differentiation, CAF-1 loss triggers a unique chromatin accessibility environment and activation of multi-lineage specific transcription factors.…”

CAF-1 deposits newly synthesized histones during DNA replication using distinct mechanisms on the leading and lagging strands

“…Chromatin Assembly Factor-1 (CAF-1) is a key regulator of chromatin assembly during DNA replication (29). CAF-1 deletion is lethal during vertebrate development (30)(31)(32), and transient CAF-1 depletion affects cell cycle progression and cell fate (27,(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). CAF-1 forms a heterotrimeric complex consisting of Cac1, Cac2 and Cac3 in yeast and p150, p60 and p48 in mammals.…”