TdIF1 Recognizes a Specific DNA Sequence through Its Helix-Turn-Helix and AT-Hook Motifs to Regulate Gene Transcription

Kubota, Takashi; Koiwai, Osamu; Hori, Katsutoshi; Watanabe, Nobuhisa; Koiwai, Kotaro

doi:10.1371/journal.pone.0066710

Cited by 7 publications

(26 citation statements)

References 46 publications

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“…TdIF1 binds to an AT‐tract through its AT‐hook (Kubota et al . ), and AT‐tracts were expectedly identified in these candidate sequences (Fig. S1B, motif3, motif4 and motif7 in Supporting Information).…”

Section: Resultsmentioning

confidence: 95%

“…We previously identified an AT‐tract and 5′‐TGCATG‐3′ as potential TdIF1‐binding sites by in vitro SELEX screening and showed that TdIF1 regulates the expression of RAB20 , which was identified as one of the TdIF1‐targets using cisRED (Kubota et al . ). To identify TdIF1‐binding sequences and TdIF1‐targets in vivo , we carried out ChIP‐seq analyses using 293T cells expressing an epitope‐tagged TdIF1 and the tag‐specific antibody (Fig.…”

Section: Resultsmentioning

confidence: 97%

“…Interestingly, this motif is highly similar to the TdIF1‐binding sequence identified by SELEX (Kubota et al . ), 5′‐TGCATG‐3′. There is an additional ‘G’ between A and T, in the in vivo target sequence, 5′‐TGCAGTG‐3′.…”

Section: Resultsmentioning

confidence: 99%

“…We conducted in vitro SELEX analyses and showed that TdIF1 binds to AT‐tract and 5′‐GNTGCATG‐3′ through the AT‐hook and helix‐turn‐helix (HTH), respectively, present in TdIF1 (Kubota et al . ). Other emerging results also support the idea that TdIF1 functions in transcription.…”

Section: Introductionmentioning

confidence: 97%

“…We found RAB20 as a TdIF1‐target gene on the basis of computational analysis using cisRED (Kubota et al . ). However, this approach cannot cover all of the TdIF1‐regulated genes.…”

Section: Introductionmentioning

confidence: 97%

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Definition of the transcription factor TdIF1 consensus‐binding sequence through genomewide mapping of its binding sites

et al. 2015

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TdIF1 was originally identified as a protein that directly binds to terminal deoxynucleotidyltransferase, TdT. Through in vitro selection assays (SELEX), we recently showed that TdIF1 recognizes both AT-tract and a specific DNA sequence motif, 5 0 -TGCATG-3 0 , and can upregulate the expression of RAB20 through the latter motif. However, whether TdIF1 binds to these sequences in the cells has not been clear and its other target genes remain to be identified. Here, we determined in vivo TdIF1-binding sequences (TdIF1-invivoBMs) on the human chromosomes through ChIP-seq analyses. The result showed a 160-base pair cassette containing 'AT-tract~palindrome (inverted repeat)~AT-tract' as a likely target sequence of TdIF1. Interestingly, the core sequence of the palindrome in the TdIF1-invivoBMs shares significant similarity to the above 5 0 -TGCATG-3 0 motif determined by SELEX in vitro. Furthermore, spacer sequences between AT-tract and the palindrome contain many potential transcription factor binding sites. In luciferase assays, TdIF1 can up-regulate transcription activity of the promoters containing the TdIF1-invivoBM, and this effect is mainly through the palindrome. Clusters of this motif were found in the potential target genes. Gene ontology analysis and RT-qPCR showed the enrichment of some candidate targets of TdIF1 among the genes involved in the regulation of ossification. Potential modes of transcription activation by TdIF1 are discussed.

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Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

“…We found RAB20 as a TdIF1‐target gene on the basis of computational analysis using cisRED (Kubota et al . ). However, this approach cannot cover all of the TdIF1‐regulated genes.…”

Section: Introductionmentioning

confidence: 97%

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Definition of the transcription factor TdIF1 consensus‐binding sequence through genomewide mapping of its binding sites

et al. 2015

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TdIF1: a putative oncogene in NSCLC tumor progression

Zhang

Wang

Huang

et al. 2018

Sig Transduct Target Ther

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TdT-interacting factor 1 (TdIF1) is a ubiquitously expressed DNA- and protein-binding protein that directly binds to terminal deoxynucleotidyl transferase (TdT) polymerase. Little is known about the functional role of TdIF1 in cancer cellular signaling, nor has it previously been identified as aberrant in any type of cancer. We report here for the first time that TdIF1 is abundantly expressed in clinical lung cancer patients and that high expression of TdIF1 is associated with poor patient prognosis. We further established that TdIF1 is highly expressed in human non-small cell lung cancer (NSCLC) cell lines compared to a normal lung cell line. shRNA-mediated gene silencing of TdIF1 resulted in the suppression of proliferation and anchorage-independent colony formation of the A549 adenocarcinoma cell line. Moreover, when these TdIF1-silenced cells were used to establish a mouse xenograft model of human NSCLC, tumor size was greatly reduced. These data suggest that TdIF1 is a potent regulator of lung tumor development. Several cell cycle-related and tumor growth signaling pathways, including the p53 and HDAC1/2 pathways, were identified as participating in the TdIF1 signaling network by in silico analysis. Microarray, transcriptome and protein-level analyses validated p53 and HDAC1/2 modulation upon TdIF1 downregulation in an NSCLC cellular model. Moreover, several other cell cycle regulators were affected at the transcript level by TdIF1 silencing, including an increase in CDKN1A/p21 transcripts. Taken together, these results indicate that TdIF1 is a bona fide tumor-promoting factor in NSCLC and a potential target for therapy.

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The histone deacetylase complex MiDAC regulates a neurodevelopmental gene expression program

Mondal

Jin

Kallappagoudar

et al. 2020

Preprint

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MiDAC is a recently identified histone deacetylase (HDAC) complex. While other HDAC complexes have been implicated in neurogenesis, the physiological role of MiDAC remains unknown. Here, we show that MiDAC constitutes an important regulator of neural differentiation. We demonstrate that MiDAC functions as a modulator of a neurodevelopmental gene expression program and binds to important regulators of neurite outgrowth. On the one hand, MiDAC upregulates gene expression by mediating the removal of H4K20ac on the promoters and enhancers of pro-neural genes such as those encoding the secreted ligands SLIT3 and NETRIN1 (NTN1). Conversely, MiDAC inhibits gene expression by reducing H3K27ac on promoterproximal and -distal elements of negative regulators of neurogenesis. Furthermore, loss of MiDAC results in neurite outgrowth defects that can be rescued by supplementation with SLIT3 and/or NTN1. These findings indicate a crucial role for MiDAC in regulating the ligands of the SLIT3 and NTN1 signaling axes to ensure the proper integrity of neurite development.

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TdIF1 Recognizes a Specific DNA Sequence through Its Helix-Turn-Helix and AT-Hook Motifs to Regulate Gene Transcription

Cited by 7 publications

References 46 publications

Definition of the transcription factor TdIF1 consensus‐binding sequence through genomewide mapping of its binding sites

Definition of the transcription factor TdIF1 consensus‐binding sequence through genomewide mapping of its binding sites

TdIF1: a putative oncogene in NSCLC tumor progression

The histone deacetylase complex MiDAC regulates a neurodevelopmental gene expression program

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