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Ssb1 and Ssb2 have essential and overlapping functions in adult stem cell homeostasis - granulocyte-macrophage progenitor data.

ABSTRACT: The single-stranded DNA binding proteins SSB1 and SSB2 are crucial regulators of the DNA damage response, however the overlapping functions of these related proteins is incompletely understood. We generated mice where both Ssb1 and Ssb2 were constitutively or conditionally deleted. Constitutive Ssb1/Ssb2 double knockout (DKO) caused early embryonic lethality, while conditional Ssb1/Ssb2 double knockout (cDKO) in adult mice resulted in acute lethality due to bone marrow failure and intestinal atrophy featured by stem and progenitor cell depletion. cDKO cells exhibited increased replication stress, R-loop accumulation, genome wide double strand breaks and cytosolic single-stranded DNA. Transcriptional profiling of cDKO cells revealed activation of p53 DNA damage and interferon responses. Hematopoietic stem and progenitor cells in cDKO mice showed enforced cell cycling, with subsequent apoptotic cell death. Collectively, these results demonstrate that Ssb1 and Ssb2 have compensatory functions in maintaining genomic stability and are collectively necessary for adult stem cell homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE75226 | GEO | 2016/01/01

SECONDARY ACCESSION(S): PRJNA302848

REPOSITORIES: GEO

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Ssb1 and Ssb2 have essential and overlapping functions in adult stem cell homeostasis - granulocyte-macrophage progenitor data.

Project description:The single-stranded DNA binding proteins SSB1 and SSB2 are crucial regulators of the DNA damage response, however the overlapping functions of these related proteins is incompletely understood. We generated mice where both Ssb1 and Ssb2 were constitutively or conditionally deleted. Constitutive Ssb1/Ssb2 double knockout (DKO) caused early embryonic lethality, while conditional Ssb1/Ssb2 double knockout (cDKO) in adult mice resulted in acute lethality due to bone marrow failure and intestinal atrophy featured by stem and progenitor cell depletion. cDKO cells exhibited increased replication stress, R-loop accumulation, genome wide double strand breaks and cytosolic single-stranded DNA. Transcriptional profiling of cDKO cells revealed activation of p53 DNA damage and interferon responses. Hematopoietic stem and progenitor cells in cDKO mice showed enforced cell cycling, with subsequent apoptotic cell death. Collectively, these results demonstrate that Ssb1 and Ssb2 have compensatory functions in maintaining genomic stability and are collectively necessary for adult stem cell homeostasis. Single colour, Illumina MouseRef-8 v2.0 Beadarrays.

2016-07-03 | E-GEOD-75226 | biostudies-arrayexpress

Ssb1 and Ssb2 have essential and overlapping functions in adult stem cell homeostasis - megakaryocyte-erythroid progenitor data.

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Ssb1/2-IntS complexes maintain splicing integrity and genomic stability through regulating RNA Polymerase II mediated snRNA levels

Project description:Ssb1(NABP2/OBFC2A) and Ssb2 (NABP1/OBFC2B) are two closely related proteins that show functional redundancies supported by their existence in two separate subcomplexes with identical proteins. Ssb1 knockout causes perinatal lethality in mice, Ssb2 knockout does not associate with any observable phenotypes, however, double knockout of both Ssb1/2 causes embryonically lethality. Notably, conditional loss of both in adult mice leads to acute lethality due to bone marrow and gut failure. Here, we further demonstrate that the overlapping essential function of both Ssb1/2 is through their prime binding partner IntS3, a member of the multiprotein complex called the Integrator. The Integrator complex interacts with the largest subunit of RNA Polymerase II and is required for processing and termination of small nuclear RNAs (snRNAs). Here, we provide a firsthand evidence that the stability of the Integrator complex is compromised in mouse-embryonic fibroblasts (MEFs) with compound loss of both Ssbs. We further demonstrate that these MEFs show overexpression of unprocessed snRNAs which forces the cells to express alternative spliced variants of genes that are required for transcription and cell cycle regulation. This phenotype closely phenocopies loss of core integrator subunit, IntS11 as well as splicing components B and C. Interestingly, the phenotype gets partially restored by overexpression of wildtype Ssb1 but not by the Ssb-mutant defective in binding integrator subunit, IntS3, demonstrating the essential roles of Ssb1/2 in the maintenance of the Integrator complex and thereby, genomic stability.

2022-03-11 | GSE155240 | GEO

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Multi-omics analyses demonstrate a critical role for EHMT1 methyltransferase in transcriptionalrepression during oogenesis

Project description:EHMT1 (also known as GLP) is a multifunctional protein, best known for its role as an H3K9me1 and H3K9me2 methyltransferase through its reportedly obligatory dimerization with EHMT2 (also known as G9A). Here, we investigated the role of EHMT1 in the oocyte in comparison to EHMT2 using oocyte-specific conditional knockout mouse models (Ehmt2 cKO, Ehmt1cKO, Ehmt1/2 cDKO), with ablation from the early phase of oocyte growth. Loss of EHMT1 in Ehmt1 cKO and Ehmt1/2 cDKO oocytes recapitulated meiotic defects observed in the Ehmt2 cKO; however, there was a significant impairment in oocyte maturation and developmental competence in Ehmt1 cKO and Ehmt1/2 cDKO oocytes beyond that observed in the Ehmt2cKO. Consequently, loss of EHMT1 in oogenesis results, upon fertilization, in mid-gestation embryonic lethality. To identify H3K9 methylation and other meaningful biological changes in each mutant to explore the molecular functions of EHMT1 and EHMT2, we performed immunofluorescence imaging, multi-omics sequencing, and mass spectrometry (MS)–based proteome analyses in cKO oocytes. Although H3K9me1 was depleted only upon loss of EHMT1, H3K9me2 was decreased, and H3K9me2-enriched domains were eliminated equally upon loss of EHMT1 or EHMT2. Furthermore, there were more significant changes in the transcriptome, DNA methylome, and proteome in Ehmt1/2 cDKO than Ehmt2 cKO oocytes, withtranscriptional derepression leading to increased protein abundance and local changes in genic DNA methylation in Ehmt1/2 cDKO oocytes. Together, our findings suggest that EHMT1 contributes to local transcriptional repression in the oocyte, partially independent of EHMT2, and is critical for oogenesis and oocyte developmental competence

2023-01-30 | PXD030265 | Pride

GLP is critical for oogenesis exhibiting a G9A-independent role in transcriptional repression

Project description:GLP (EHMT1) functions as an H3K9me1 and H3K9me2 methyltransferase through its reportedly obligatory dimerization with G9A (EHMT2). Here, we investigated the role of GLP in oocyte and embryo development in comparison to G9A using oocyte-specific conditional knockout mouse models (G9a cKO, Glp cKO, G9a-Glp cDKO). Loss of GLP in oogenesis severely impairs oocyte maturation, fertilization and embryo development, resulting in lethality before embryonic day E12.5. In contrast, loss of G9A has a milder effect with a proportion of embryos producing viable offspring. The Glp cKO also showed loss of G9A protein and, hence, was phenotypically very similar to the G9a-Glp cDKO. H3K9me2 was equally depleted in all cKO genotypes, whereas H3K9me1 was decreased only in Glp cKO and G9a-Glp cDKO oocytes. Furthermore, the transcriptome, DNA methylome and proteome were markedly more affected in G9a-Glp cDKO than G9a cKO oocytes, demonstrating that in the absence of GLP there are widespread epigenetic and gene expression changes in the oocyte independent of H3K9me2. Gene dysregulation with coupled changes in DNA methylation suggest localised loss of chromatin repression, resulting in upregulated protein expression. Together, our findings demonstrate that GLP can function independently of G9A in the oocyte and is required for oocyte developmental competence.

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