KAT2A complexes ATAC and SAGA play unique roles in cell maintenance and identity in hematopoiesis and leukemia

Author notes: *E.F. and S.W. contributed equally to this study. ChIP-seq and A-seq data have been deposited in GEO (accession numbers GSE128902 and GSE128512). Send data sharing requests via e-mail to the corresponding author. The full-text version of this article contains a data supplement.Copyright © 2021 The Authors. Epigenetic histone modifiers are key regulators of cell fate decisions in normal and malignant hematopoiesis. Their enzymatic activities are of particular significance as putative therapeutic targets in leukemia. In contrast, less is known about the contextual role in which those enzymatic activities are exercised, and specifically, how different macromolecular complexes configure the same enzymatic activity with distinct molecular and cellular consequences. We focus on KAT2A, a lysine acetyltransferase responsible for Histone 3 Lysine 9 acetylation, which we recently identified as a dependence in Acute Myeloid Leukemia stem cells, and that participates in 2 distinct macromolecular complexes: Ada Two- A-Containing (ATAC) and Spt-Ada-Gcn5-Acetyltransferase (SAGA). Through analysis of human cord blood hematopoietic stem cells and progenitors, and of myeloid leukemia cells, we identify unique respective contributions of the ATAC complex to regulation of biosynthetic activity in undifferentiated self-renewing cells, and of the SAGA complex to stabilisation or correct progression of cell type-specific programs with putative preservation of cell identity. Cell type and stage-specific dependencies on ATAC and SAGA-regulated programs explain multi-level KAT2A requirements in leukemia and in erythroid lineage specification and development. Importantly, they set a paradigm against which lineage specification and identity can be explored across developmental stem cell systems.Rosetrees Trust PhD Studentship; Kendall Leukaemia Fund Intermediate Fellowship (KKL888); Leuka John Goldman Fellowship for Future Science (2017); Wellcome Trust/University of Cambridge ISSF Grant; Lady Tata Memorial Trust PhD Studentship; Trinity Henry Barlow Trust Studentship; NIH RO1 grant (1R01GM131626-01); Agence Nationale de la Recherche (ANR) Program grants (AAPG2019 PICen, PRCI AAPG2019 EpiCAST, ANR-10-LABX-0030-INRT, frame program Investissements d’Avenir ANR-10IDEX-0002-02); Brunel University

Electron trapping and reinjection in prepulse-shaped gas targets for laser-plasma accelerators

A novel mechanism for injection, emittance selection, and postacceleration for laser wakefield electron acceleration is identified and described. It is shown that a laser prepulse can create an ionized plasma filament through multiphoton ionization and this heats the electrons and ions, driving an ellipsoidal blast-wave aligned with the laser-axis. The subsequent high-intensity laser-pulse generates a plasma wakefield which, on entering the leading edge of the blast-wave structure, encounters a sharp reduction in electron density, causing density down-ramp electron injection. The injected electrons are accelerated to ∼2  MeV within the blast-wave. After the main laser-pulse has propagated past the blast-wave, it drives a secondary wakefield within the homogenous background plasma. On exiting the blast-wave structure, the preaccelerated electrons encounter these secondary wakefields, are retrapped, and accelerated to higher energies. Due to the longitudinal extent of the blast-wave, only those electrons with small transverse velocity are retrapped, leading to the potential for the generation of electron bunches with reduced transverse size and emittance

Specialised gas targets for controlled injection of electrons into laser-driven wakefields.

Laser-driven wakefield acceleration within capillary discharge waveguides has been used to generate high quality electron bunches with GeV scale energies. However, uncontrolled self-injection by wave-breaking of non-linear plasma waves can lead to large fluctuations in energy spread, divergence and charge of the accelerated bunches. Specialised plasma targets with tailored density profiles offer the possibility to overcome these issues by controlling the injection and acceleration process. This requires precise manipulation of the longitudinal density profile. Therefore we developed plasma targets based on a capillary structure with multiple gas in- and outlets operated at steady-state gas flow. Here we give a detailed overview of the target concept and discuss preliminary experimental results for ionisation injection obtained by utilising these targets at the ASTRA laser at Rutherford Appleton Lab