Pax5 maintains cellular identity by repressing gene expression throughout B cell differentiation.

The transcription factor Pax5 is required for many aspects of B-lymphopoiesis including lineage commitment, immunoglobulin rearrangement, pre-BCR signalling and mature B cell survival. Pax5 regulates B cell lineage commitment by concurrently activating B cell specific gene expression as well as suppressing the expression of genes associated with non-B cell fates. The identity of the molecular targets of Pax5-mediated gene repression is the subject of much current interest. Recent studies have documented the essential nature of the Pax5 repression of the stem cell transcriptional program, as well as the silencing of lineage inappropriate gene expression, for B cell development. Surprisingly the repression of genes by Pax5 continues throughout lymphopoiesis, with the loss of Pax5 in mature B cell resulting in the reactivation of the same Pax5 targets during plasma cell differentiation. These recent insights into the mechanism of action of Pax5 in controlling B cell identity will be discussed

Initiation of plasma-cell differentiation is independent of the transcription factor Blimp-1.

SummaryBlimp-1 is considered an essential regulator of the terminal differentiation of B cells into antibody-secreting plasma cells. We show here that Rag1−/− mice reconstituted with fetal liver cells homozygous for a DNA-binding-deficient mutant of Prdm1 (the gene encoding Blimp-1) lack a defined plasma-cell compartment, yet show detectable amounts of all immunoglobulin isotypes. In vitro analysis revealed that Blimp-1 is not required for the initiation of antibody secretion but is essential for subsequent high immunoglobulin production. Blimp-1-independent differentiation was blocked at a preplasmablast stage characterized by decreased Pax5 expression and the activation of plasma-cell genes. Analysis of Blimp-1-sufficient differentiation revealed a phase prior to Blimp-1 expression in which several genes normally repressed by Pax5 are re-expressed, suggesting that plasma-cell differentiation is initiated by the inhibition of Pax5 function. Our results indicate that full plasma-cell differentiation but not commitment to the plasma-cell fate requires the expression of functional Blimp-1

Pax5 maintains cellular identity by repressing gene expression throughout B cell differentiation.

The transcription factor Pax5 is required for many aspects of B-lymphopoiesis including lineage commitment, immunoglobulin rearrangement, pre-BCR signalling and mature B cell survival. Pax5 regulates B cell lineage commitment by concurrently activating cell specific gene expression as well as suppressing the expression of genes associated with non-B cell fates. The identity of the molecular targets of Pax5-mediated gene repression is the subject of much current interest. Recent studies have documented the essential nature of the Pax5 mediated repression of the stem cell transcriptional program, as well as the silencing of lineage inappropriate gene expression, for B cell development. Surprisingly the repression of genes by Pax5 continues throughout lymphopoiesis, with the loss of Pax5 in mature B cell resulting in the reactivation of the same Pax5 targets during plasma cell differentiation. These recent insights into the mechanism of action of Pax5 in controlling B cell identity will be discussed

Innate Immunity Champions: The Diverse Functions of Macrophages

Macrophages are instrumental in maintaining tissue homeostasis, modulating inflammation, and driving regeneration. The advent of omics techniques has led to the identification of numerous tissue-specific macrophage subtypes, thereby introducing the concept of the “macrophage niche”. This paradigm underscores the ability of macrophages to adapt their functions based on environmental cues, such as tissue-specific signals. This adaptability is closely linked to their metabolic states, which are crucial for their function and role in health and disease. Macrophage metabolism is central to their ability to switch between proinflammatory and anti-inflammatory states. In this regard, environmental factors, including the extracellular matrix, cellular interactions, and microbial metabolites, profoundly influence macrophage behavior. Moreover, diet and gut microbiota significantly impact macrophage function, with nutrients and microbial metabolites influencing their activity and contributing to conditions like inflammatory bowel disease. Targeting specific macrophage functions and their metabolic processes is leading to the development of novel treatments for a range of chronic inflammatory conditions. The exploration of macrophage biology enriches our understanding of immune regulation and holds the promise of innovative approaches to managing diseases marked by inflammation and immune dysfunction, offering a frontier for scientific and clinical advancement.</p

Innate Immunity Champions: The Diverse Functions of Macrophages

Macrophages are instrumental in maintaining tissue homeostasis, modulating inflammation and driving regeneration. The advent of omics techniques has led to the identification of numerous tissue-specific macrophage subtypes, thereby introducing the concept of the “macrophage niche”. This paradigm underscores the ability of macrophages to adapt their functions based on environmental cues, such as tissue-specific signals. This adaptability is closely linked to their metabolic states, which are crucial for their function and role in both health and disease. Macrophage metabolism is central to their ability to switch between pro-inflammatory and anti-inflammatory states. In this regard, environmental factors, including the extracellular matrix, cellular interactions, and microbial metabolites, profoundly influence macrophage behaviour. Moreover, diet and gut microbiota significantly impact macrophage function, with nutrients and microbial metabolites influencing their activity and contributing to conditions like inflammatory bowel disease. Targeting specific macrophage functions and their metabolic processes is leading to the development of novel treatments for a range of chronic inflammatory conditions. The exploration of macrophage biology enriches our understanding of immune regulation and holds the promise of innovative approaches to manage diseases marked by inflammation and immune dysfunction, offering a frontier for scientific and clinical advancement

HDAC7 Is a Repressor of Myeloid Genes Whose Downregulation Is Required for Transdifferentiation of Pre-B Cells into Macrophages

B lymphopoiesis is the result of several cell-commitment, lineage-choice, and differentiation processes. Every differentiation step is characterized by the activation of a new, lineage-specific, genetic program and the extinction of the previous one. To date, the central role of specific transcription factors in positively regulating these distinct differentiation processes to acquire a B cell-specific genetic program is well established. However, the existence of specific transcriptional repressors responsible for the silencing of lineage inappropriate genes remains elusive. Here we addressed the molecular mechanism behind repression of non-lymphoid genes in B cells. We report that the histone deacetylase HDAC7 was highly expressed in pre-B cells but dramatically down-regulated during cellular lineage conversion to macrophages. Microarray analysis demonstrated that HDAC7 re-expression interfered with the acquisition of the gene transcriptional program characteristic of macrophages during cell transdifferentiation; the presence of HDAC7 blocked the induction of key genes for macrophage function, such as immune, inflammatory, and defense response, cellular response to infections, positive regulation of cytokines production, and phagocytosis. Moreover, re-introduction of HDAC7 suppressed crucial functions of macrophages, such as the ability to phagocytose bacteria and to respond to endotoxin by expressing major pro-inflammatory cytokines. To gain insight into the molecular mechanisms mediating HDAC7 repression in pre-B cells, we undertook co-immunoprecipitation and chromatin immunoprecipitation experimental approaches. We found that HDAC7 specifically interacted with the transcription factor MEF2C in pre-B cells and was recruited to MEF2 binding sites located at the promoters of genes critical for macrophage function. Thus, in B cells HDAC7 is a transcriptional repressor of undesirable genes. Our findings uncover a novel role for HDAC7 in maintaining the identity of a particular cell type by silencing lineage-inappropriate genes

HOX-mediated LMO2 expression in embryonic mesoderm is recapitulated in acute leukaemias

The Lim Domain Only 2 (LMO2) leukaemia oncogene encodes an LIM domain transcriptional cofactor required for early haematopoiesis. During embryogenesis, LMO2 is also expressed in developing tail and limb buds, an expression pattern we now show to be recapitulated in transgenic mice by an enhancer in LMO2 intron 4. Limb bud expression depended on a cluster of HOX binding sites, while posterior tail expression required the HOX sites and two E-boxes. Given the importance of both LMO2 and HOX genes in acute leukaemias, we further demonstrated that the regulatory hierarchy of HOX control of LMO2 is activated in leukaemia mouse models as well as in patient samples. Moreover, Lmo2 knock-down impaired the growth of leukaemic cells, and high LMO2 expression at diagnosis correlated with poor survival in cytogenetically normal AML patients. Taken together, these results establish a regulatory hierarchy of HOX control of LMO2 in normal development, which can be resurrected during leukaemia development. Redeployment of embryonic regulatory hierarchies in an aberrant context is likely to be relevant in human pathologies beyond the specific example of ectopic activation of LMO2