The BTB transcription factors ZBTB11 and ZFP131 maintain pluripotency by repressing pro-differentiation genes

Garipler, Görkem; Lu, Congyi; Morrissey, Alexis; Lopez-Zepeda, Lorena S.; Pei, Yingzhen; Vidal, Simon E.; Fiore, Ana Paula Zen Petisco; Aydın, Begüm; Stadtfeld, Matthias; Ohler, Uwe; Mahony, Shaun; Sanjana, Neville E.; Mazzoni, Esteban O.

doi:10.1016/j.celrep.2022.110524

Cited by 13 publications

(14 citation statements)

References 99 publications

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“…18 Embryonic stem cells lacking ZBTB11 lost clonal form and exhibited reduced proliferation. 37 All these findings support the essential role of ZBTB11 in the proliferation of normal cells. Because ZBTB11 was highly expressed in BC tissue compared with normal bladder tissue, we hypothesized that ZBTB11 may be important for BC cell proliferation and cisplatin resistance.…”

Section: Discussionsupporting

confidence: 53%

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Knockdown of ZBTB11 impedes R‐loop elimination and increases the sensitivity to cisplatin by inhibiting DDX1 transcription in bladder cancer

et al. 2022

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Introduction Bladder cancer (BC) is one of the most common malignant cancers, with poor prognosis and high incidence. Cisplatin is the standard chemotherapy for muscle invasive bladder cancer; however, chemotherapy resistance remains a major challenge. Moreover, oncogenic signalling and the specific mechanisms underlying cisplatin resistance in BC remain largely unclear Methods In this study, RT‐PCR, Western blot, immunofluorescence, and immunohistochemistry were used to measure gene and protein expression. Colony formation assay and flow cytometry were performed to evaluate the proliferation of BC cells. Gene set enrichment analysis was performed to identify the function in which ZBTB11 was involved. Luciferase and chromatin immunoprecipitation experiments were performed to determine the transcriptional regulation mechanism of ZBTB11. The effects of ZBTB11 on the malignant phenotypes of BC cells were examined in vitro and in vivo Results The results showed that ZBTB11 was remarkably upregulated in BC tissues, which was associated with poor prognosis in patients with BC. Furthermore, we found that knockdown of ZBTB11 remarkably inhibited the proliferation and tumorigenesis of BC cells by inducing apoptosis. Mechanistically, the knockdown of ZBTB11 transcriptionally inhibited DDX1 to suppress R‐loop clearance, resulting in DNA damage in BC cells. Importantly, the ZBTB11/DDX1 axis is required for the chemotherapy resistance of BC cells to cisplatin Conclusion Our findings not only reveal an underlying mechanism by which the ZBTB11/DDX1 axis promotes the tumorigenesis of BC but also provide a potential target for a combination strategy of cisplatin‐based chemotherapy for BC.

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Section: Discussionsupporting

confidence: 53%

“…ZBTB11 gene inactivation leads to impaired mitochondrial respiratory function, resulting in proliferation arrest and cell death 18 . Embryonic stem cells lacking ZBTB11 lost clonal form and exhibited reduced proliferation 37 . All these findings support the essential role of ZBTB11 in the proliferation of normal cells.…”

Section: Discussionmentioning

confidence: 60%

Knockdown of ZBTB11 impedes R‐loop elimination and increases the sensitivity to cisplatin by inhibiting DDX1 transcription in bladder cancer

et al. 2022

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“…The samples were then compared using the CRISPTimeR algorithm that identifies hits in dropout screens (Garipler et al, 2022). Depletion of multiple sgRNAs for a given gene yields a low CRISPTimeR score and identifies this gene as a positive regulator; conversely, sgRNA enrichment produces a high CRISPTimeR score corresponding to a negative regulator.…”

Section: Resultsmentioning

confidence: 99%

“…After normalization, a mixed linear model was used to evaluate gene enrichment or depletion as described (Garipler et al, 2022). Briefly, the model has the following formula: Where Counts i is the log counts of gene i ; α <[:] is the intercept for sgRNA j of gene i ; β A is the overall estimate for Time and ɛ is the error.…”

Section: Methodsmentioning

confidence: 99%

Genome-wide analysis of dendritic cell differentiation

Tiniakou

Hsu

Lopez-Zepeda

et al. 2022

Preprint

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SummaryDendritic cells (DCs) are immune sentinel cells that comprise antigen-presenting conventional DCs (cDCs) and cytokine-producing plasmacytoid DCs (pDCs). Cytokine Flt3 ligand (Flt3L) supports the proliferation of hematopoietic progenitors, and is also necessary and sufficient for DC differentiation. Here we characterized the spontaneous differentiation of a Flt3L-dependent murine progenitor cell line into pDCs and “myeloid” cDCs (cDC2s), and interrogated it using a genome-wide CRISPR/Cas9 dropout screen. The screen revealed multiple regulators of DC differentiation including the glycosylphosphatidylinositol transamidase complex, the Nieman-Pick type C cholesterol transporter and arginine methyltransferase Carm1; the role of Carm1 in pDC and cDC2 differentiation was confirmed by conditional targeting in vivo. We also found that negative regulators of mTOR signaling, including the subunits of TSC and GATOR1 complexes, restricted progenitor growth but enabled DC differentiation. The results provide a comprehensive forward genetic analysis of DC differentiation, and help explain how the opposing processes of proliferation and differentiation could be driven by the same cytokine.

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“…These ZBTB proteins can regulate the binding of p53 to the promoter of the P21CIP1 gene that encodes the CDK2 kinase inhibitor p21. Various ZBTB proteins such as PATZ1 (ZBTB19), ZBTB2, ZBTB11, ZBTB12, ZNF131 (ZBTB35) are also involved in stem cell reprogramming, either maintaining or antagonizing pluripotency [26][27][28][29][30]. This function possibly involves a collaboration with p53 which has also been implicated in this process [31].…”

Section: Zinc Finger Proteins; the Zbtb Familymentioning

confidence: 99%

Dimerization choice and alternative functions of ZBTB transcription factors

Barakat,

Ezen,

Devecioğlu

et al. 2023

The FEBS Journal

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Zinc Finger DNA‐binding domain‐containing proteins are the most populous family among eukaryotic transcription factors. Among these, members of the BTB domain‐containing ZBTB sub‐family are mostly known for their transcriptional repressive functions. In this Viewpoint article, we explore molecular mechanisms that potentially diversify the function of ZBTB proteins based on their homo and heterodimerization, alternative splicing and post‐translational modifications. We describe how the BTB domain is as much a scaffold for the assembly of co‐repressors, as a domain that regulates protein stability. We highlight another mechanism that regulates ZBTB protein stability: phosphorylation in the zinc finger domain. We explore the non‐transcriptional, structural roles of ZBTB proteins and highlight novel findings that describe the ability of ZBTB proteins to associate with poly adenosine ribose in the nucleus during the DNA damage response. Herein, we discuss the contribution of BTB domain scaffolds to the formation of transcriptional repressive complexes, to chromosome compartmentalization and their non‐transcriptional, purely structural functions in the nucleus.

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The BTB transcription factors ZBTB11 and ZFP131 maintain pluripotency by repressing pro-differentiation genes

Cited by 13 publications

References 99 publications

Knockdown of ZBTB11 impedes R‐loop elimination and increases the sensitivity to cisplatin by inhibiting DDX1 transcription in bladder cancer

Knockdown of ZBTB11 impedes R‐loop elimination and increases the sensitivity to cisplatin by inhibiting DDX1 transcription in bladder cancer

Genome-wide analysis of dendritic cell differentiation

Dimerization choice and alternative functions of ZBTB transcription factors

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