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A SIRT7-dependent acetylation switch regulates early B-cell differentiation and lineage commitment through PAX5

ABSTRACT: B lymphopoiesis is a key developmental event orchestrated by a complex combinatorial action of lineage-specific transcription factors. In early B cell progenitors, lineage commitment is directly mediated by the master regulator PAX5, whose deficiency is commonly associated with B cell Acute Lymphoblastic Leukemia (B-ALL). Despite its essential role in mammalian immunity, the regulatory mechanisms that control PAX5 function remain largely unknown. Here we show that NAD+-dependent enzyme SIRT7 coordinates B cell development progression through PAX5. We have identified a SIRT7-dependent regulatory switch based on dynamic deacetylation of a single PAX5 residue, which controls its activity and thereby B cell fate. While a PAX5K198 acetylated mimic is incapable of inducing both B cell development and identity due to reduced protein stability and impaired binding to chromatin, deacetylation of this residue boosts PAX5 activity, leading to massive gene repression and in vivo restoration of B cell commitment but not differentiation. These findings suggest an unexpected uncoupling of hematopoietic differentiation and lineage commitment. Further supporting the functional relevance of the SIRT7-PAX5 axis, the interplay between both factors is conserved in human B-ALL, where high SIRT7 expression is an independent good prognostic factor. Our findings unveil a crucial mechanism in the regulation of B cell production based on the control of PAX5 function and underscore the key role of Sirtuins in the regulation of the immune system.

INSTRUMENT(S): orbitrap

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): B Cell, Blood

SUBMITTER: Joan Josep Bech-Serra

LAB HEAD: Alex Vaquero

PROVIDER: PXD046457 | Pride | 2024-09-20

REPOSITORIES: Pride

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	3579_CT_AVAQ001_1B.raw	Raw
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	3579_CT_AVAQ001_3B.raw	Raw
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A SIRT7-dependent acetylation switch regulates early B-cell differentiation and lineage commitment through Pax5

Project description:B lymphopoiesis is a key developmental event orchestrated by a complex combinatorial action of lineage-specific transcription factors. In early B cell progenitors, lineage commitment is directly mediated by the master regulator Pax5, whose deficiency is commonly associated with B cell Acute Lymphoblastic Leukemia (B-ALL). Despite its essential role in mammalian immunity, the regulatory mechanisms that control Pax5 function remain largely unknown. Here we show that NAD+-dependent enzyme SIRT7 coordinates B cell development progression through regulation of Pax5 function. We have identified a SIRT7-dependent regulatory switch based on dynamic deacetylation of a single Pax5 residue, which controls its activity and thereby B cell fate. While a PAX5K198 acetylated mimic is incapable of inducing both B cell development and identity due to reduced protein stability and impaired binding to chromatin, deacetylation of this residue boosts Pax5 activity, leading to massive gene repression and restoration of B cell commitment but not differentiation in vivo. These findings suggest an unexpected uncoupling of hematopoietic differentiation and lineage commitment. Further supporting the functional relevance of the SIRT7-PAX5 axis, the interplay between both factors is largely conserved in human B-ALL, where high SIRT7 expression is an independent good prognostic factor. Our findings unveil a crucial mechanism in the regulation of B-cell production based on the control of Pax5 function and underscore the key role of Sirtuins in the regulation of the immune system.

2024-09-19 | GSE246370 | GEO

Essential role of the Pax5 C-terminal domain in controlling B cell commitment and development

Project description:Pax5 controls B-cell commitment, development and immunity by repressing B-lineage-inappropriate genes and activating B-cell-specific genes. In addition to the N-terminal DNA-binding paired domain, Pax5 contains a conserved octapeptide, partial homeodomain and C-terminal sequences with transactivating and inhibitory potential. To understand how the C-terminal domains of Pax5 contribute to the repression and activation function of Pax5, we performed Pax5 pulldown combined with mass spectrometry to identify coactivator or corepressor complexes that bind to the C-terminal regions of Pax5.

2023-08-24 | PXD040424 | Pride

Gene expression analysis of Pax5-/- proB cells transduced with control or EBF retrovirus.

Project description:We have determined that sustained expression of EBF suppresses alternate lineage genes independently of Pax5. Keywords: Transcription factor EBF restricts alternate lineage options and promotes B cell fate commitment independently of Pax5.

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The transcription factor Pax5 regulates its target genes by recruiting chromatin-modifying proteins in committed B cells

Project description:Pax5 is a critical regulator of B cell commitment. Here we identified direct Pax5 target genes by streptavidin-mediated ChIP-chip analysis of pro-B cells expressing in vivo biotinylated Pax5. By binding to promoters and enhancers, Pax5 directly regulates the expression of multiple transcription factor, cell surface receptor and signal transducer genes. One of the newly identified enhancers was shown by transgenic analysis to confer Pax5-dependent B-cell-specific activity to the Nedd9 gene controlling B cell trafficking. Profiling of histone modifications in Pax5-deficient and committed wild-type pro-B cells demonstrated that Pax5 induces active chromatin at activated target genes, while eliminating active chromatin at repressed genes in committed pro-B cells. Pax5 rapidly induces these chromatin and transcription changes by recruiting chromatin-remodeling, histone-modifying and basal transcription factor complexes to its target genes. These data provide novel insight into the regulatory network and epigenetic regulation, by which Pax5 controls B cell commitment. Analysis of chromatin and TF binding in rag2-/- and pax5-/- rag2-/- pro-B cells. Chip-Chip with 1-3 experiments for each antibody and celltype combination.

2012-03-29 | E-GEOD-28373 | biostudies-arrayexpress

The transcription factor Pax5 regulates its target genes by recruiting chromatin-modifying proteins in committed B cells

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Project description:The transcription factor Pax5 is essential for B cell commitment in the mouse, where it represses lineage-inappropriate gene expression, while simultaneously activating the B cell gene expression program. We have performed a global gene expression screen of wild type and Pax5-deficient pro-B cells in an attempt to identify the crucial Pax5 targets in early B-lymphopoiesis. We have also included Rag1-/- and wild type (+/+) proB cells starved of the cytokine IL-7 for 4 hours as controls. Rag1-/- proB cells are incapable of further differentiation due to an absence of immunoglobulin recombination and IL-7 is the major cytokine regulating proB cell growth. Keywords: comparison of genetically modified cell-lines

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Project description:Multiple transcription factors regulate B cell commitment, which coordinates with myeloid–erythroid lineage differentiation. One such factor, NF-kB, has long been speculated to regulate early B cell development; however, this issue remains controversial. IKKa is required for splenic B cell maturation, but not for bone marrow (BM) B cell development. Here, we unexpectedly found defective BM B cell development and an increased myeloid–erythroid lineages in kinase-dead IKKa (KA/KA) knock-in mice. Markedly increased cytosolic p100, an NF-kB2 inhibitory form, and reduced nuclear NF-kB p65, RelB, p50, and p52, as well as IKKa, was observed in KA/KA splenic and BM B cells. Several B- and myeloid–erythroid-cell regulators, including Pax5, were deregulated in KA/KA BM B cells. Using fetal liver and BM congenic transplants, and IKKa deletion from early hematopoietic cells in mice, this defect was identified as B cell intrinsic and as an early event during hematopoiesis. Re-expression of IKKa, Pax5, or combined NF-kB molecules promoted B cell development, but repressed myeloid–erythroid cell differentiation in KA/KA BM B cells. Together, these results demonstrate that IKKa regulates B-lineage commitment via combined canonical and noncanonical NF-kB transcriptional activity to target Pax5 expression during hematopoiesis.

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2005-04-17 | E-MEXP-270 | biostudies-arrayexpress

SIRT7-dependent deacetylation of the U3-55k protein controls pre-rRNA processing [CLIP-Seq]

Project description:SIRT7 is an NAD+-dependent protein deacetylase with important roles in ribosome biogenesis and cell proliferation. Previous studies have established that SIRT7 is associated with RNA polymerase I, interacts with pre-rRNA and promotes rRNA synthesis. Here we show that SIRT7 is also associated with snoRNAs that are involved in pre-rRNA processing and rRNA maturation. Knockdown of SIRT7 impairs U3 snoRNA-dependent early cleavage steps that are necessary for generation of 18S rRNA. Mechanistically, SIRT7 deacetylates U3-55k, a core component of the U3 snoRNP complex, and reversible acetylation of U3-55k modulates the association of U3-55k with U3 snoRNA. Deacetylation by SIRT7 enhances U3-55k binding to U3 snoRNA, which is a prerequisite for pre-rRNA processing. Under stress conditions, SIRT7 is released from nucleoli, leading to hyperacetylation of U3-55k and attenuation of prerRNA processing. The results reveal a multifaceted role of SIRT7 in ribosome biogenesis, regulating both transcription and processing of rRNA. CLIP-seq was performed in Flag-SIRT7-293T cells.

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