CIBZ Regulates Mesodermal and Cardiac Differentiation of by Suppressing T and Mesp1 Expression in Mouse Embryonic Stem Cells

Kotoku, Tomomi; Kosaka, Koji; Nishio, Makoto; Ishida, Yasumasa; Kawaichi, Masashi; Matsuda, Eishou

doi:10.1038/srep34188

Cited by 16 publications

(25 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, ZBTB38 has been shown to repress overall transcription by inhibiting expression of MCM10, a component of the pre-replication complex [20]. Additionally, ZBTB38 can, directly or indirectly, regulate cell cycle progression, cellular differentiation, and apoptosis [21][22][23][24][25]. In contrast to this speculation, we demonstrate that, despite high levels of expression in germinal center B lymphocytes and plasma cells, ZBTB38 deficiency does not impair primary or secondary antibody responses to T cell-dependent model immunogens.…”

Section: Introductioncontrasting

confidence: 58%

ZBTB38 is dispensable for antibody responses

Wong

Bhattacharya

2020

PLoS ONE

View full text Add to dashboard Cite

Members of the broad complex, tram track, bric-a-brac and zinc finger (BTB-ZF) family of transcription factors, such as BCL-6, ZBTB20, and ZBTB32, regulate antigen-specific B cell differentiation, plasma cell longevity, and the duration of antibody production. We found that ZBTB38, a different member of the BTB-ZF family that binds methylated DNA at CpG motifs, is highly expressed by germinal center B cells and plasma cells. To define the functional role of ZBTB38 in B cell responses, we generated mice conditionally deficient in this transcription factor. Germinal center B cells lacking ZBTB38 dysregulated very few genes relative to wild-type and heterozygous littermate controls. Accordingly, mice with hematopoietic-specific deletion of Zbtb38 showed normal germinal center B cell numbers and antibody responses following immunization with hapten-protein conjugates. Memory B cells from these animals functioned normally in secondary recall responses. Despite expression of ZBTB38 in hematopoietic stem cells, progenitors and mature myeloid and lymphoid lineages were also present in normal numbers in mutant mice. These data demonstrate that ZBTB38 is dispensable for hematopoiesis and antibody responses. These conditional knockout mice may instead be useful in defining the functional importance of ZBTB38 in other cell types and contexts.

show abstract

Section: Introductioncontrasting

confidence: 58%

ZBTB38 is dispensable for antibody responses

Wong

Bhattacharya

2020

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…In vitro, ZBTB38 has preferential affinity for two different sets of methylated consensus sequences, which it binds through two different sets of Zinc fingers ( 10–11 ). As ZBTB38 represses transcription ( 9 , 12 , 22 , 49 ), its role against oxidative stress could entail dampening the expression of methylated genes. Potential candidates include genes regulating the production of ROS by mitochondria, and their detoxification.…”

Section: Discussionmentioning

confidence: 99%

Stabilization of the methyl-CpG binding protein ZBTB38 by the deubiquitinase USP9X limits the occurrence and toxicity of oxidative stress in human cells

Miotto

Marchal

Adelmant

et al. 2018

Nucleic Acids Research

View full text Add to dashboard Cite

Reactive oxygen species (ROS) are a byproduct of cell metabolism, and can also arise from environmental sources, such as toxins or radiation. Depending on dose and context, ROS have both beneficial and deleterious roles in mammalian development and disease, therefore it is crucial to understand how these molecules are generated, sensed, and detoxified. The question of how oxidative stress connects to the epigenome, in particular, is important yet incompletely understood. Here we show that an epigenetic regulator, the methyl-CpG-binding protein ZBTB38, limits the basal cellular production of ROS, is induced by ROS, and is required to mount a proper response to oxidative stress. Molecularly, these functions depend on a deubiquitinase, USP9X, which interacts with ZBTB38, deubiquitinates it, and stabilizes it. We find that USP9X is itself stabilized by oxidative stress, and is required together with ZBTB38 to limit the basal generation of ROS, as well as the toxicity of an acute oxidative stress. Our data uncover a new nuclear target of USP9X, show that the USP9X/ZBTB38 axis limits, senses and detoxifies ROS, and provide a molecular link between oxidative stress and the epigenome.

show abstract

“…Herein, we hypothesized that DNMTi might have an effect on the transcription factors that bind methylated DNA, so we evaluated the impact of 5-azacytidine on the function and expression of the zinc finger and BTB domain containing protein ZBTB38, that binds to methyl-CpGs 26 – 28 . ZBTB38 is involved in various cellular functions, including the regulation of DNA replication, the control of gene expression and the regulation of cell proliferation and differentiation 26 , 29 – 32 . We observed that 5-azacytidine causes the down-regulation of ZBTB38 protein expression.…”

Section: Introductionmentioning

confidence: 99%

Depletion of ZBTB38 potentiates the effects of DNA demethylating agents in cancer cells via CDKN1C mRNA up-regulation

et al. 2018

View full text Add to dashboard Cite

DNA methyltransferase inhibitor (DNMTi) treatments have been used for patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and have shown promising beneficial effects in some other types of cancers. Here, we demonstrate that the transcriptional repressor ZBTB38 is a critical regulator of the cellular response to DNMTi. Treatments with 5-azacytidine, or its derivatives decitabine and zebularine, lead to down-regulation of ZBTB38 protein expression in cancer cells, in parallel with cellular damage. The depletion of ZBTB38 by RNA interference enhances the toxicity of DNMTi in cell lines from leukemia and from various solid tumor types. Further we observed that inactivation of ZBTB38 causes the up-regulation of CDKN1C mRNA, a previously described indirect target of DNMTi. We show that CDKN1C is a key actor of DNMTi toxicity in cells lacking ZBTB38. Finally, in patients with MDS a high level of CDKN1C mRNA expression before treatment correlates with a better clinical response to a drug regimen combining 5-azacytidine and histone deacetylase inhibitors. Collectively, our results suggest that the ZBTB38 protein is a target of DNMTi and that its depletion potentiates the toxicity of DNMT inhibitors in cancer cells, providing new opportunities to enhance the response to DNMT inhibitor therapies in patients with MDS and other cancers.

show abstract

CIBZ Regulates Mesodermal and Cardiac Differentiation of by Suppressing T and Mesp1 Expression in Mouse Embryonic Stem Cells

Cited by 16 publications

References 53 publications

ZBTB38 is dispensable for antibody responses

ZBTB38 is dispensable for antibody responses

Stabilization of the methyl-CpG binding protein ZBTB38 by the deubiquitinase USP9X limits the occurrence and toxicity of oxidative stress in human cells

Depletion of ZBTB38 potentiates the effects of DNA demethylating agents in cancer cells via CDKN1C mRNA up-regulation

Contact Info

Product

Resources

About