CtBP-interacting BTB Zinc Finger Protein (CIBZ) Promotes Proliferation and G1/S Transition in Embryonic Stem Cells via Nanog

Nishii, Tomonori; Oikawa, Yu; Ishida, Yasumasa; Kawaichi, Masashi; Matsuda, Eishou

doi:10.1074/jbc.m111.333856

Cited by 26 publications

(37 citation statements)

References 33 publications

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“…Noxa and Puma, their expression levels were decreased in Zbtb38 lentivirus-treated SCI mice from day 4 after injection, whereas Bak expression was only significantly lower on the days 2 of testing when Zbtb38 expression was rescued (Figure 5 ). Zbtb38 has been implicated to promote proliferation and G1/S transition in mouse embryonic stem cells [ 24 ]. We next determined cell cycle with or without Zbtb38 lentivirus administration.…”

Section: Resultsmentioning

confidence: 99%

Zbtb38 is a novel target for spinal cord injury

Cai

Zhang

et al. 2017

Oncotarget

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Spinal cord injury (SCI) is currently incurable since treatments applied to clinic are limited to minimizing secondary complications and the mechanisms of injury-induced spinal cord damage are poorly understood. Zbtb38, also called CIBZ, is highly expressed in spinal cord and it functions as a negative regulator in SCI-induced apoptosis. We show here that Zbtb38 is downregulated under endoplasmic reticulum (ER) stress, which promotes ER stress-associated apoptosis in human bone marrow neuroblastoma cells. In the traumatic SCI mice, ER stress presented in injured spinal cord induced repression of Zbtb38 expression and triggered Zbtb38-mediated apoptosis. ChIP-QPCR analysis revealed that ATF4, an ER-stress inducible transcription factor, directly activated Zbtb38 transcription by binding to the Zbtb38 promoter. However, this binding was significantly reduced following SCI, leading to a sharp decrease in Zbtb38 expression. Restoring Zbtb38 function in injured spinal cord by injection of lentivirus containing Zbtb38 into SCI mice, significantly alleviated secondary damage of spinal cord with decreased ER stress-associated apoptosis and partially recovered spinal cord functions. These findings demonstrate that restoration of Zbtb38 expression can reduce secondary tissue damage after SCI, and suggest that a therapeutic strategy for targeting Zbtb38 may promote functional recovery of spinal cord for patients with SCI.

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Section: Resultsmentioning

confidence: 99%

Zbtb38 is a novel target for spinal cord injury

Cai

Zhang

et al. 2017

Oncotarget

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“…To determine whether loss of CIBZ affects ESC differentiation, we used CIBZ knockout (CIBZ −/− ) ESC line, which was maintained in the undifferentiated state, as described previously 18 , and the effects of CIBZ knockout were determined using semi-quantitative PCR. These experiments showed no changes in Nanog, Sox2, and Oct3/4 expression in the absence of CIBZ during ESC differentiation ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We then demonstrated that loss of CIBZ induces apoptosis in murine cells 16 , and that CIBZ negatively regulates myogenic differentiation by binding and inhibiting the myogenin promoter via its zinc finger domains 17 . Because CIBZ is highly expressed in ESCs and is critical for ESC proliferation 18 , we hypothesized that CIBZ plays a role in the regulation of ESC differentiation.…”

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confidence: 99%

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

Kotoku¹,

Kosaka

Nishio

et al. 2016

Sci Rep

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The molecular mechanisms underlying mesodermal and cardiac specification from embryonic stem cells (ESCs) are not fully understood. Here, we showed that the BTB domain-containing zinc finger protein CIBZ is expressed in mouse ESCs but is dramatically downregulated during ESC differentiation. CIBZ deletion in ESCs induced specification toward mesoderm phenotypes and their differentiation into cardiomyocytes, whereas overexpression of CIBZ delayed these processes. During ESC differentiation, CIBZ loss-and-gain-of-function data indicate that CIBZ negatively regulates the expressions of Brachyury (T) and Mesp1, the key transcriptional factors responsible for the specification of mammalian mesoderm and cardiac progenitors, respectively. Chromatin immunoprecipitation assays showed that CIBZ binds to T and Mesp1 promoters in undifferentiated ESCs, and luciferase assays indicate that CIBZ suppresses T and Mesp1 promoters. These findings demonstrate that CIBZ is a novel regulator of mesodermal and cardiac differentiation of ESCs, and suggest that CIBZ-mediated cardiac differentiation depends on the regulation of these two genes.

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“…It was further demonstrated that, depending on the gene context, the C-terminal ZBTB38 ZFs participate in modulating transcriptional outcomes (37). These findings have significant implications for delineating the overall biological function of ZBTB38, given that its transcriptional activities have been linked to a number of core cellular processes such as cellular proliferation (38), apoptosis (35,39), and replication/genomic stability (40).…”

mentioning

confidence: 97%

Structural insights into methylated DNA recognition by the C-terminal zinc fingers of the DNA reader protein ZBTB38

Hudson¹,

Whitby

Buck‐Koehntop³

2018

Journal of Biological Chemistry

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Edited by Karin Musier-Forsyth Methyl-CpG-binding proteins (MBPs) are selective readers of DNA methylation that play an essential role in mediating cellular transcription processes in both normal and diseased cells. This physiological function of MBPs has generated significant interest in understanding the mechanisms by which these proteins read and interpret DNA methylation signals. Zinc finger and BTB domain-containing 38 (ZBTB38) represents one member of the zinc finger (ZF) family of MBPs. We recently demonstrated that the C-terminal ZFs of ZBTB38 exhibit methyl-selective DNA binding within the ((A/G)TmCG(G/A)(mC/ T)(G/A)) context both in vitro and within cells. Here we report the crystal structure of the first four C-terminal ZBTB38 ZFs (ZFs 6-9) in complex with the previously identified methylated consensus sequence at 1.75 Å resolution. From the structure, methyl-selective binding is preferentially localized at the 5 mCpG site of the bound DNA, which is facilitated through a series of base-specific interactions from residues within the ␣helices of ZF7 and ZF8. ZF6 and ZF9 primarily stabilize ZF7 and ZF8 to facilitate the core base-specific interactions. Further structural and biochemical analyses, including solution NMR spectroscopy and electrophoretic mobility gel shift assays, revealed that the C-terminal ZFs of ZBTB38 utilize an alternative mode of mCpG recognition from the ZF MBPs structurally evaluated to date. Combined, these findings provide insight into the mechanism by which this ZF domain of ZBTB38 selectively recognizes methylated CpG sites and expands our understanding of how ZF-containing proteins can interpret this essential epigenetic mark.

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CtBP-interacting BTB Zinc Finger Protein (CIBZ) Promotes Proliferation and G1/S Transition in Embryonic Stem Cells via Nanog

Cited by 26 publications

References 33 publications

Zbtb38 is a novel target for spinal cord injury

Zbtb38 is a novel target for spinal cord injury

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

Structural insights into methylated DNA recognition by the C-terminal zinc fingers of the DNA reader protein ZBTB38

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