5 research outputs found
CBX7 Induces Self-Renewal of Human Normal and Malignant Hematopoietic Stem and Progenitor Cells by Canonical and Non-canonical Interactions
In this study, we demonstrate that, among all five CBX
Polycomb proteins, only CBX7 possesses the ability
to control self-renewal of human hematopoietic
stem and progenitor cells (HSPCs). Xenotransplantation of CBX7-overexpressing HSPCs resulted in
increased multi-lineage long-term engraftment and
myelopoiesis. Gene expression and chromatin analyses revealed perturbations in genes involved in
differentiation, DNA and chromatin maintenance,
and cell cycle control. CBX7 is upregulated in acute
myeloid leukemia (AML), and its genetic or pharmacological repression in AML cells inhibited proliferation and induced differentiation. Mass spectrometry
analysis revealed several non-histone protein interactions between CBX7 and the H3K9 methyltransferases SETDB1, EHMT1, and EHMT2. These CBX7-
binding proteins possess a trimethylated lysine
peptide motif highly similar to the canonical CBX7
target H3K27me3. Depletion of SETDB1 in AML cells
phenocopied repression of CBX7. We identify CBX7
as an important regulator of self-renewal and uncover
non-canonical crosstalk between distinct pathways,
revealing therapeutic opportunities for leukemia
The Canadian Earth System Model version 5 (CanESM5.0.3)
The Canadian Earth System Model version 5 (CanESM5) is a global model developed to simulate historical climate change and variability, to make centennial-scale projections of future climate, and to produce initialized seasonal and decadal predictions. This paper describes the model components and their coupling, as well as various aspects of model development, including tuning, optimization, and a reproducibility strategy. We also document the stability of the model using a long control simulation, quantify the model's ability to reproduce large-scale features of the historical climate, and evaluate the response of the model to external forcing. CanESM5 is comprised of three-dimensional atmosphere (T63 spectral resolution equivalent roughly to 2.8 degrees) and ocean (nominally 1 degrees) general circulation models, a sea-ice model, a land surface scheme, and explicit land and ocean carbon cycle models. The model features relatively coarse resolution and high throughput, which facilitates the production of large ensembles. CanESM5 has a notably higher equilibrium climate sensitivity (5.6 K) than its predecessor, CanESM2 (3.7 K), which we briefly discuss, along with simulated changes over the historical period. CanESM5 simulations contribute to the Coupled Model Intercomparison Project phase 6 (CMIP6) and will be employed for climate science and service applications in Canada