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Bone marrow-induced Mef2c deficiency delays B cell development and alters the expression of key B cell regulatory proteins

ABSTRACT: The Mef2 family transcriptional regulator Mef2c is highly expressed in maturing bone marrow and peripheral mature B cells. To evaluate the role of this transcription factor in B cell development, we generated a B cell specific conditional deletion of Mef2c using the Mb-1-Cre transgene that is expressed during the early stages of immunoglobulin rearrangement. Young mice possessing this defect demonstrated a significant impairment in B cell numbers in bone marrow and spleen. This phenotype was evident in all B cell subsets; however, as the animals mature, the deficit in the peripheral mature B cell compartments was overcome. The absence of Mef2c in mature B cells led to unique CD23+ and CD23- subsets that were evident in Mef2c KO primary samples as well as cultured, differentiated B cells but not in WT cell populations. Genome wide expression analysis of immature and mature B cells lacking Mef2c indicated altered expression for a number of key regulatory proteins for B cell function including Ciita, CD23, Cr1/Cr2, and Tnfsf4. Chromatin immunoprecipitation analysis confirmed Mef2c binding to the promoters of these genes indicating a direct link between the presence (or absence) of Mef2c and altered transcriptional control in mature B cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE34210 | GEO | 2012/06/01

SECONDARY ACCESSION(S): PRJNA149677

REPOSITORIES: GEO

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Bone marrow-induced Mef2c deficiency delays B cell development and alters the expression of key B cell regulatory proteins

Project description:The Mef2 family transcriptional regulator Mef2c is highly expressed in maturing bone marrow and peripheral mature B cells. To evaluate the role of this transcription factor in B cell development, we generated a B cell specific conditional deletion of Mef2c using the Mb-1-Cre transgene that is expressed during the early stages of immunoglobulin rearrangement. Young mice possessing this defect demonstrated a significant impairment in B cell numbers in bone marrow and spleen. This phenotype was evident in all B cell subsets; however, as the animals mature, the deficit in the peripheral mature B cell compartments was overcome. The absence of Mef2c in mature B cells led to unique CD23+ and CD23- subsets that were evident in Mef2c KO primary samples as well as cultured, differentiated B cells but not in WT cell populations. Genome wide expression analysis of immature and mature B cells lacking Mef2c indicated altered expression for a number of key regulatory proteins for B cell function including Ciita, CD23, Cr1/Cr2, and Tnfsf4. Chromatin immunoprecipitation analysis confirmed Mef2c binding to the promoters of these genes indicating a direct link between the presence (or absence) of Mef2c and altered transcriptional control in mature B cells. Four samples are submitted.

2012-05-31 | E-GEOD-34210 | biostudies-arrayexpress

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HYPK controls stability and catalytic activity of the N-terminal acetyltransferase A in Arabidopsis thaliana

Project description:The ribosome-tethered N-terminal acetyltransferase A (NatA) acetylates 52% of soluble proteins in Arabidopsis thaliana. This co-translational shielding of the N-terminus stabilizes diverse cytosolic plant proteins. The Huntingtin yeast partner K (HYPK) facilitates NatA activity in planta, but in vitro, the N-terminal a-helix1 of HYPK inhibits NatA in the ternary NatA/HYPK complex. Consequently, the mechanism of HYPK function in plants was unknown. To understand the regulatory function of HYPK at the molecular level, we genetically engineered CRISPR/Cas9 mutants expressing either a non-functional HYPK (hypk-cr1) or an N-terminally deleted HYPK version (hypk-cr2). Like NatA-activity-depleted mutants, the hypk-cr1 and –cr2 mutants were more tolerant to drought stress and suffered from global proteome destabilization. Surprisingly, we found that absence of HYPK led to destabilization of the NatA subunits in leaves but not in roots of hypk-cr1. Further genetic and molecular evidence demonstrated that the stability of NatA subunits in leaves is mainly controlled by the C-terminal UBA domain of HYPK. While retaining the UBA domain, NatA activity was still impaired in hypk-cr2 leaves, implying that the N terminus of HYPK also contributes to the regulation of NatA activity. Furthermore, crossing of hypk-cr1 with a NatA-depleted mutant uncovered that HYPK promotes NatA activity not only by stabilizing NatA. Taken together, the activity-promoting function of the HYPK N-terminus depends on the binding of HYPK to NatA via the UBA domain, and is critical for NatA substrates starting with various amino acids. Our findings improve our understanding of the NatA regulatory subunit HYPK.

2024-01-22 | PXD047700 | Pride

HYPK controls stability and catalytic activity of the N-terminal acetyltransferase A in Arabidopsis thaliana

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Transcriptional profile of B cells isolated from neonatal and adult hearts

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Expression data from murine bone marrow-resident plasma cells and spleen mature follicular B cells

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