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 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE246370 | GEO | 2024/09/19

REPOSITORIES: GEO