Biology subjects

Raifer, H.

Publications and source records attributed to Raifer, H..

3 recordsLinked to original sources

bioRxiv2022

Enhanced methionine cycle suppresses naïve CD8+ T-cell maturation

The metabolic pathways controlling naive CD8+ T (Tn) cell maturation following thymic egress remain mostly undefined. This is important because immature Tn are a major component of peripheral immune tolerance in newborns and under lymphopenia. In this study we demonstrate that TMRM, a mitochondrial membrane potential marker, could be applied to rapidly identify an immature Tn cell population in the periphery. Applying this marker to perform metabolic and proteomic analysis, we show that immature Tn cells maintain accelerated methionine cycle in respect to mature Tn. This unique metabolic state was associated with restricted Tbx21 locus and diminished immune response in vitro and in vivo. Following our findings, we demonstrate that inhibition of methionine cycle leads to rapid functional maturation of Tn and recovery of immune response to stimuli. Our work provides insight into the way the rate of methionine cycling regulates T cell maturation, opening a path for metabolic manipulation of immune tolerance.

immunology↗

bioRxiv2022

IRF4 deficiency vulnerates B cell progeny for leukemogenesis via somatically acquired Jak3 mutations conferring IL-7 hypersensitivity

The processes leading from disturbed B cell development to adult B cell progenitor acute lymphoblastic leukemia (BCP-ALL) are poorly understood. Here, we describe Irf4-/- mice as prone to developing BCP-ALL with age. Irf4-/- preB-I cells exhibited impaired differentiation but enhanced proliferation in response to IL-7, along with reduced retention in the IL-7 providing bone marrow niche due to decreased CXCL12 responsiveness. Thus selected, preB-I cells acquired Jak3 mutations, probably following irregular AID activity, resulting in malignant transformation. We demonstrate heightened IL-7 sensitivity due to Jak3 mutants, devise a model to explain it and describe structural and functional similarities to Jak2 mutations often occurring in human Ph-like ALL. Finally, targeting JAK signaling with Ruxolitinib in vivo prolonged survival of mice bearing established Irf4-/- leukemia. Intriguingly, organ infiltration including leukemic meningeosis was selectively reduced without affecting blood blast counts. In this work, we present spontaneous leukemogenesis following IRF4 deficiency with potential implications for high-risk BCP-ALL in adult humans.

cancer biology↗

bioRxiv2020

Ush regulates hemocyte-specific gene expression, fatty acid metabolism and cell cycle progression and cooperates with dNuRD to orchestrate hematopoiesis

The generation of lineage-specific gene expression programmes that alter proliferation capacity, metabolic profile and cell type-specific functions during differentiation from multipotent stem cells to specialised cell types is crucial for development. During differentiation gene expression programmes are dynamically modulated by a complex interplay between sequence-specific transcription factors, associated cofactors and epigenetic regulators. Here, we study U-shaped (Ush), a multi-zinc finger protein that maintains the multipotency of stem cell-like hemocyte progenitors during Drosophila hematopoiesis. Using genomewide approaches we reveal that Ush binds to promoters and enhancers and that it controls the expression of three gene classes that encode proteins relevant to stem cell-like functions and differentiation: cell cycle regulators, key metabolic enzymes and proteins conferring specific functions of differentiated hemocytes. We employ complementary biochemical approaches to characterise the molecular mechanisms of Ush-mediated gene regulation. We uncover distinct Ush isoforms one of which binds the Nucleosome Remodeling and Deacetylation (NuRD) complex using an evolutionary conserved peptide motif. Remarkably, the Ush/NuRD complex specifically contributes to the repression of lineage-specific genes but does not impact the expression of cell cycle regulators or metabolic genes. This reveals a mechanism that enables specific and concerted modulation of functionally related portions of a wider gene expression programme. Finally, we use genetic assays to demonstrate that Ush and NuRD regulate enhancer activity during hemocyte differentiation in vivo and that both cooperate to suppress the differentiation of lamellocytes, a highly specialised blood cell type. Our findings reveal that Ush coordinates proliferation, metabolism and cell type-specific activities by isoform-specific cooperation with an epigenetic regulator.

molecular biology↗