MOZ (KAT6A) is essential for the maintenance of classically defined adult hematopoietic stem cells

Abstract

Hematopoietic stem cells (HSCs) are conventionally thought to be at the apex of a hierarchy that produces all mature cells of the blood. The quintessential property of these cells is their ability to reconstitute the entire hematopoietic system of hemoablated recipients. This characteristic has enabled HSCs to be used to replenish the hematopoietic system of patients after chemotherapy or radiotherapy. Here, we use deletion of the monocytic leukemia zinc finger gene to examine the effects of removing HSCs. Loss of MOZ in adult mice leads to the rapid loss of HSCs as defined by transplantation. This is accompanied by a reduction of the LSK-CD48CD150 and LSK-CD34Flt3 populations in the bone marrow and a reduction in quiescent cells in G Surprisingly, the loss of classically defined HSCs did not affect mouse viability, and there was no recovery of the LSK-CD48CD150 and LSK-CD34Flt3 populations 15 to 18 months after deletion. Clonal analysis of myeloid progenitors, which produce short-lived granulocytes, demonstrate that these are derived from cells that had undergone recombination at the locus up to 2 years earlier, suggesting that early progenitors have acquired extended self-renewal. Our results establish that there are essential differences in HSC requirement for steady-state blood cell production compared with the artificial situation of reconstitution after transplantation into a hemoablated host. A better understanding of steady-state hematopoiesis may facilitate the development of novel therapies engaging hematopoietic cell populations with previously unrecognized traits, as well as characterizing potential vulnerability to oncogenic transformation.

Histone Acetyltransferase KAT6A Upregulates PI3K/AKT Signaling through TRIM24 Binding

“…The mammalian KAT6A was firstly identified in AML patients (13). Previous work identified KAT6A interactions with ING5, EAF6, and BRPF1, -2, and -3 (36, 37) to form a macromolecular complex to regulate normal hematopoietic stem cell maintenance (9) and AML development (36). Recent KAT6A was revealed to be amplified and overexpressed in breast cancers, and depletion of KAT6A markedly inhibited cell proliferation and tumor growth in breast cancer through regulating estrogen receptor α expression (ERα) (14).…”

“…Lysine acetyltransferase 6A (KAT6A, also known as MYST3 and MOZ) is a MYST-family histone acetyltransferase, which controls fundamental cellular processes, including gene transcription (5), cellular senescence (6), cardiac septum development (7), memory T cell diversity (8), and maintenance of normal hematopoietic stem cells (9). Dysregulation of the KAT6A histone acetyltransferase activity or aberrant expression of KAT6A has been associated with oncogenesis in leukemia (10-13) and breast cancer (14).…”

Histone Lysine and Genomic Targets of Histone Acetyltransferases in Mammals

“…[25] Deletion of the Kat6a gene in adult mice causes a complete loss of haematopoietic stem cells [26] . However, requirements in different cell types can vary and so the conclusion ought to be restricted to the cell type(s) under examination.…”

“…Based on a binding via FOXO3 to ATM [113] MOF X chromosome Predicted Simultaneous contact of MOF with MSL1 and MSL3 leads to recruitment to chromatin, X chromosome in Drosophila [93] MOF At MLL1 bound promoters Predicted Based on interactions between MLL1 C-terminal domain and MOF zinc finger domain [92] MOF At all active gene loci Predicted Based on pronounced genome-wide loss of H4K16ac when mutated [38,39] MOF At all active gene loci Actual ChIP-seq experiments detect high positive correlation with RNA Pol II binding throughout the genome [2] MOF All promoters Actual ChIP-Seq shows NSL1 and MCRS2 bind to promoters genome-wide [94] HBO1 At origins of replication Predicted A fraction of the relatively abundant HBO1 protein associates with ORC1 in human cell extracts [29] HBO1 At most active gene loci Actual ChIP-seq experiments and based on interactions with chromatin binding proteins ING4, ING5, JADE1, JADE2, JADE3, BRPFs [27,28] HBO1 At most gene loci Actual Anti-HBO1 ChIP-seq shows binding to gene body and promoter, increased levels of binding correlate with higher gene expression [71] HBO1 At origins of replication Actual Enrichment of HBO1 at ORC1-binding sites and origins of replication [30] HBO1 At most active gene loci Predicted Based on pronounced genome-wide loss of H3K14ac when mutated [21] KAT6B At specific active gene loci Predicted Based on normal development of many organs and cell types in the KAT6B deficient state [58,59] KAT6A At specific active gene loci Predicted KAT6A null cells and embryos, absence of changes in histone acetylation genome-wide, moderate locus-specific loss of H3K9ac, normal development of many organs and cell types [26,40,41] www.advancedsciencenews.com www.bioessays-journal.com acetylation of H3K14 by HBO1 in the context of a BRPF3-containing complex around transcription start sites enables efficient activation of nearby replication origins. [30] Overall, there is strong in vivo evidence for a role of HBO1 in facilitating gene transcription and cell survival (possibly via gene transcription).…”

Hematopoietic Stem Cell Dynamics Are Regulated by Progenitor Demand: Lessons from a Quantitative Modeling Approach

“…We mimic the intrinsic HSC heterogeneity by assuming a separation between repopulating HSCs (rpHSCs), which are rarely activated during homeostasis and preferentially divide asymmetrically, and maintaining HSCs (mtHSCs), which ensure the continuous supply of progenitor cells for downstream hematopoiesis. Our model establishes a unifying framework which reproduces both the rare contribution [6] and the slow recovery of HSCs in the homeostatic situation [6,8,9,55], as well as the accelerated responses after perturbation (see references in [4]). The model extends to address the apparent increase in phenotypic HSCs as a consequence of an impaired HSC control due to the loss of cell polarity and the consequent inability of the cells to divide asymmetrically [53].…”