Temporal expression of MOF acetyltransferase primes transcription factor networks for erythroid fate

Abstract

Self-renewal and differentiation of hematopoietic stem cells (HSCs) are orchestrated by the combinatorial action of transcription factors and epigenetic regulators. Here, we have explored the mechanism by which histone H4 lysine 16 acetyltransferase MOF regulates erythropoiesis. Single-cell RNA sequencing and chromatin immunoprecipitation sequencing uncovered that MOF influences erythroid trajectory by dynamic recruitment to chromatin and its haploinsufficiency causes accumulation of a transient HSC population. A regulatory network consisting of MOF, RUNX1, and GFI1B is critical for erythroid fate commitment. GFI1B acts as a Mof activator which is necessary and sufficient for cell type-specific induction of Mof expression. Plasticity of Mof-depleted HSCs can be rescued by expression of a downstream effector, Gata1, or by rebalancing acetylation via a histone deacetylase inhibitor. Accurate timing and dosage of Mof expression act as a rheostat for the feedforward transcription factor network that safeguards progression along the erythroid fate.

Epigenetic Regulators as the Gatekeepers of Hematopoiesis

“…Defects in chromatin accessibility are associated with altered transcription programs in hematopoietic progenitor cells and disbalanced mature cell output [38]. In this sense, methods which help ascertain the chromatin landscape (Boxes 3 and 4) have emerged as powerful tools in understanding cell fate decisions along a continuous trajectory.…”

“…Given the close association of histone acetylation and active transcription, KATs (p300, CBP, MOZ GCN5, HBO1, and MOF) have been extensively studied in the context of normal and malignant hematopoiesis [38,[58][59][60][61][62][63][64][65][66][67]. For instance, the CBP-p300 family of KATs has been implicated in both HSC self-renewal and differentiation, as illustrated by specific binding of CBP/p300 to the c-Myb KIX domain which thereby regulates c-Myb-dependent gene expression [68].…”

“…Ablation of the MYST family KAT MOZ (also known as KAT6A or MYST3) has been shown to regulate various aspects of hematopoiesis, ranging from HSC proliferation to self-renewal and hematopoietic lineage commitment [62]. Likewise, the KAT MOF (also known as KAT8 or MYST1) was found to specifically influence adult hematopoiesis [38,66], while being dispensable for the highly proliferative fetal counterpart [65]. MOF orchestrates erythropoiesis through its modulation of H4K16ac and chromatin accessibility in HSCs and erythroid progenitors (MPP2 and MEP).…”

“…Removal of MOF or its enzymatic activity severely compromises erythroid differentiation in colony-formation assays. Consequently, both Mof +/− and Vav1-iCre Mof flox/flox animals suffer from anemia and display reduced numbers of erythroid progenitors and MEPs in vivo [38,66].…”

“…This is also mirrored by fluctuations in global levels of the MOF target modification H4K16ac in these cell types. Fluctuations in the expression patterns of Hdac4, Hdac2, and Sirt4 are also observed along differentiation through the erythroid lineage, raising the possibility that multiple histone acetylation sites besides H4K16ac are dynamically regulated [38].…”