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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
	3579_CT_AVAQ001_2B.raw	Raw
	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.

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A SIRT7-dependent acetylation switch regulates early B-cell differentiation and lineage commitment through Pax5

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IKKa-mediated signaling circuitry regulates early B lymphopoiesis during hematopoiesis

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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