Disruption of erythroid nuclear opening and histone release in myelodysplastic syndromes

Abstract

Mammalian terminal erythropoiesis involves several characteristic phenomena including chromatin condensation and enucleation. One of the newly identified features of terminal erythropoiesis in mouse is a dynamic nuclear opening and histone release process, which is required for chromatin condensation. However, it is unclear whether the same feature is present in human. Here, we use an in vitro human CD34‐positive hematopoietic stem and progenitor cell culture system and reveal that nuclear openings and histone release are also identified during human terminal erythropoiesis. In contrast to mouse in which each erythroblast contains a single opening, multiple nuclear openings are present in human erythroblast, particularly during the late‐stage differentiation. The nuclear opening and histone release process is mediated by caspase‐3. Inhibition of caspase‐3 blocks nuclear opening, histone release, chromatin condensation, and terminal differentiation. We confirm the finding of histone cytosolic release in paraffin‐embedded human bone marrow in vivo. Importantly, we find that patients with myelodysplastic syndrome (MDS) exhibit significant defects in histone release in the dysplastic erythroblasts. Our results reveal developmentally conserved nuclear envelop and histone dynamic changes in human terminal erythropoiesis and indicate that disruption of the histone release process plays a critical role in the pathogenesis of dyserythropoiesis in MDS.

A new role of glutathione peroxidase 4 during human erythroblast enucleation

“…In these diseases, erythroid defects leading to inaccurate reticulocyte production are heterogeneous and occur at multiple steps, including apoptosis of erythroid precursors, defective HSP70/GATA1 interaction, translation defect, aberrant splicing, oxidative stress, and anomalies in terminal differentiation involving mitophagy and nuclear condensation. [77][78][79][80] Enucleation is directly impaired during congenital dyserythropoietic anemia type (CDA) IV (OMIM #613673), a rare type of ineffective erythropoiesis leading to numerous circulating nucleated red cells. This autologous dominant disease is related to E325K mutation in KLF1, leading to expression of a variant with a strong dominant-negative effect on KLF1 regulation network.…”

Dimeric Manganese‐Catalyzed Hydroarylation and Hydroalkenylation of Unsaturated Amides

“…Consequently, exploration of new and unique catalytic activity of manganese complexes in homogeneous catalysis has gained considerable momentum in recent years . For example, with recent efforts, Mn(I)‐catalyzed C(sp 2 )−H bond activation of directed arenes, dehydrogenative coupling of alcohols and selective hydrosilylation of alkenes have opened powerful tools of preparing valuable organic compounds.…”

Manganese‐Catalyzed Oxime‐Directed ortho‐C−H Amidation in Ionic Liquids

“…More specifically, aromatic ketones are among the most important targets and synthetic building blocks; the ketone directed C−H functionalization offers an efficient protocol to prepare functionalized ketones. However, due to the weak coordinating power of ketone directing group, late transition metals such as Ru, Ir based catalysts play a leading role (Scheme a), the use of base metal catalysts in the ketone‐directed C−H activations is more challenging …”

“…Compared to late transition metals, naturally abundant first‐row early transition metals such as manganese are more sustainable catalyst systems. For ketone directed C−H activations, recently Wang and coworkers reported a C−H addition of aromatic ketones to imines . Along this line, due to the importance of aromatic amines, we have developed an Mn‐catalyzed ketone directed amidation using organo azides as amidation agents (Scheme c) .…”