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Lin28b augments protein synthesis to control B cell positive selection early in life [RNA-seq]

ABSTRACT: In this study, we identify elevated protein synthesis as a defining characteristic of early life B cell development and a determinant for the qualitative switch in B cell output whereby self-reactive CD5+ B-1 cells becomes censored in postnatal mice This is in part mediated by the heterochronic RNA binding protein LIN28B. To identify Lin28b-dependent, stage specific effects, B cell progenitors at different developmental stages were sorted and analyzed by RNA-seq

ORGANISM(S): Mus musculus

PROVIDER: GSE217786 | GEO | 2022/11/16

REPOSITORIES: GEO

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Lin28b augments protein synthesis to control B cell positive selection early in life [RIP-seq]

Project description:In this study, we identify elevated protein synthesis as a defining characteristic of early life B cell development and a determinant for the qualitative switch in B cell output whereby self-reactive CD5+ B-1 cells becomes censored in postnatal mice This is in part mediated by the heterochronic RNA binding protein LIN28B. To identify Lin28b-dependent, stage specific effects, B cell progenitors at different developmental stages were sorted and analyzed by RNA-seq

2022-11-16 | GSE217787 | GEO

Lin28b controls a neonatal to adult switch in B cell positive selection

Project description:The ability of B-1 cells to become positively selected into the mature B cell pool, despite being weakly self-reactive, has puzzled the field since its initial discovery. Here, we explore changes in B cell positive selection as a function of developmental time by exploiting a link between CD5 surface levels and the natural occurrence of self-reactive B cell receptors (BCRs) in BCR wildtype mice. We show that the heterochronic RNA-binding protein Lin28b potentiates a neonatal mode of B cell selection characterized by enhanced overall positive selection and the developmental progression of CD5+ immature B cells in particular. Importantly, Lin28b achieves this through amplifying the CD19/PI3K/c-Myc positive feedback loop and ectopic Lin28b expression restores both positive selection and mature B cell numbers in CD19–/– adult mice. Thus, the temporally restricted expression of Lin28b alters the rules for B cell selection during ontogeny through modulating tonic signaling. We propose that this neonatal mode of B cell selection represents a cell intrinsic cue to accelerate the de novo establishment of the adaptive immune system and incorporate a layer of natural antibody mediated immunity throughout life.

2019-08-27 | GSE135603 | GEO

Lin28b augments protein synthesis to control B cell positive selection early in life.

Project description:Lin28b augments protein synthesis to control B cell positive selection early in life.

| PRJNA900541 | ENA

Lin28b augments protein synthesis to control B cell positive selection early in life.

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-11-16 | GSE217788 | GEO

Lin28b augments protein synthesis to control B cell positive selection early in life [RIP-seq]

Project description:Lin28b augments protein synthesis to control B cell positive selection early in life [RIP-seq]

| PRJNA900544 | ENA

Lin28b augments protein synthesis to control B cell positive selection early in life [RNA-seq]

Project description:Lin28b augments protein synthesis to control B cell positive selection early in life [RNA-seq]

| PRJNA900545 | ENA

The OTUD6B-LIN28B-MYC axis determines cell cycle progression in multiple myeloma

Project description:Deubiquitylases (DUBs) remove ubiquitin from proteins. In the context of cancer, their inhibition can induce the degradation of oncoproteins, that may otherwise be “undruggable”. Multiple myeloma (MM) is the second most common hematological malignancy with poor outcome and high sensitivity towards ubiquitin-proteasome-system (UPS) inhibitory therapies. However, the role of DUBs in MM pathophysiology and therapy has remained elusive. Starting from genetic screening for DUB dependencies in MM, we here identify OTUD6B as a central vulnerability in MM that drives the G1/S cell cycle transition by means of deubiquitylating and stabilizing LIN28B subsequent to LIN28B phosphorylation. LIN28B regulates miRNA biogenesis and exerts high expression in embryonic stem cells that becomes re-established in certain tumors, including MM. Binding of LIN28B at G1/S activates OTUD6B, which otherwise remains in a catalytically inactive state. As a consequence, stabilized LIN28B drives MYC expression via inhibition of let7 microRNAs, which in turn allows for a rapid transition of MM cells from G1 to S phase. Analyses of primary MM patient samples reveal a positive correlation of OTUDB6B expression with poor outcome, high MYC expression and MYC target gene induction, suggesting that high MYC levels in MM result from an activation of the OTUD6B-LIN28B nexus. Together, we here specify phosphorylation and cell cycle-dependent substrate binding as a means by which OTUD6B becomes activated to drive the G1/S transition via the LIN28B-MYC axis and nominate OTUD6B and LIN28B as actionable vulnerabilities in MM.

2022-10-12 | PXD027480 | Pride

C/EBPβ-LIP regulates the let-7/Lin28b circuit to induce cancer-type metabolic reprogramming

Project description:The RNA binding protein Lin28b is highly expressed during embryogenesis but its expression declines in adult tissues, and aberrant expression of Lin28b is associated with tumour development and maintenance. Lin28b regulates the translation of several glycolytic and mitochondrial enzymes in order to enhance cellular metabolism and energy production. Lin28b is repressed by let-7 family microRNAs in a reciprocal negative regulatory circuitry where Lin28b supresses maturation of let-7. This circuitry obtains input from master regulators such as MYC that transcriptionally upregulates Lin28b, which is required for let-7 suppression and proliferation. Not much is known of how this circuitry is regulated through transcription of the let-7 microRNAs. Here we show that the transcription factor C/EBPβ-LIP induces aerobic glycolysis and mitochondrial respiration reminiscent to cancer cell metabolism. By integrating transcriptome, proteome and metabolic flux analysis we reveal that this LIP-induced metabolic reprogramming is dependent on Lin28b and that LIP enhances Lin28b expression through transcriptional repression of the let-7 microRNA family. Transgenic mice overexpressing LIP have reduced levels of let-7 in bone marrow, skin and spleen, which is associated with induction of Lin28b and hyperplasia. This study establishes LIP as a regulator of the let-7/Lin28b regulatory circuitry and we hypothesize that the LIP-controlled let-7/Lin28b regulation is involved in the de-regulation of tissue homeostasis and tumourigenesis.

2019-11-12 | PXD010095 | Pride

LIN28B and colon cancer

Project description:This SuperSeries is composed of the following subset Series: GSE26334: Expression data from LoVo colon cancer lines +/- constitutive LIN28B expression GSE26335: Expression data from xenograft tumors derived from LoVo colon cancer lines +/- constitutive LIN28B expression Refer to individual Series

2010-12-29 | E-GEOD-26336 | biostudies-arrayexpress

Expression data from LoVo colon cancer lines +/- constitutive LIN28B expression

Project description:We sought to elucidate the molecular mechanisms whereby LIN28B functions by comparing the gene expression profile of cells constitutively expressing LIN28B to empty vector controls. Accordingly, we performed microarray analysis on total RNA isolated from empty vector LoVo and LIN28B-expressing LoVo colon cancer cell lines. Constitutive LIN28B expression was achieved in the LoVo (ATCC #CCL-229) colon cancer cell line via retroviral transduction of MSCV-PIG-LIN28B. Contol = empty vector MSCV-PIG.

2010-12-29 | E-GEOD-26334 | biostudies-arrayexpress

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