Faculty Opinions recommendation of The role of a Williams-Beuren syndrome-associated helix-loop-helix domain-containing transcription factor in activin/nodal signaling.

AbstractMNT, a transcription factor of the MXD family, is an important modulator of the oncoprotein MYC. Both MNT and MYC are basic-helix–loop–helix proteins that heterodimerize with MAX in a mutually exclusive manner, and bind to E-boxes within regulatory regions of their target genes. While MYC generally activates transcription, MNT represses it. However, the molecular interactions involving MNT as a transcriptional regulator beyond the binding to MAX remain unexplored. Here we demonstrate a novel MAX-independent protein interaction between MNT and REL, the oncogenic member of the NF-κB family. REL participates in important biological processes and it is altered in a variety of tumors. REL is a transcription factor that remains inactive in the cytoplasm in an inhibitory complex with IκB and translocates to the nucleus when the NF-κB pathway is activated. In the present manuscript, we show that MNT knockdown triggers REL translocation into the nucleus and thus the activation of the NF-κB pathway. Meanwhile, MNT overexpression results in the repression of IκBα, a bona fide REL target. Both MNT and REL bind to the IκBα gene on the first exon, suggesting its regulation as an MNT–REL complex. Altogether our data indicate that MNT acts as a repressor of the NF-κB pathway by two mechanisms: (1) retention of REL in the cytoplasm by MNT interaction, and (2) MNT-driven repression of REL-target genes through an MNT–REL complex. These results widen our knowledge about MNT biological roles and reveal a novel connection between the MYC/MXD and NF-κB pathways, two of the most prominent pathways in cancer.

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Olig2 regulates p53-mediated apoptosis, migration and invasion of melanoma cells

Scientific Reports ◽

10.1038/s41598-021-87438-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ji Eun Lee ◽

Sungjin Ahn ◽

Haengdueng Jeong ◽

Seungchan An ◽

Cheol Hwan Myung ◽

...

Keyword(s):

Transcription Factor ◽

Enzyme Activity ◽

Malignant Cell ◽

Melanoma Cells ◽

Migration And Invasion ◽

High Recurrence Rate ◽

Metastatic Progression ◽

Helix Loop Helix ◽

The Central Nervous System

AbstractMelanoma is a disease with a high recurrence rate and poor prognosis; therefore, the need for targeted therapeutics is steadily increasing. Oligodendrocyte transcription factor2 (Olig2) is a basic helix-loop-helix transcription factor that is expressed in the central nervous system during embryonic development. Olig2 is overexpressed in various malignant cell lines such as lung carcinoma, glioma and melanoma. Olig2 is known as a key transcription factor that promotes tumor growth in malignant glioma. However, the role of Olig2 in melanoma is not well characterized. We analyzed the role of Olig2 in apoptosis, migration, and invasion of melanoma cells. We confirmed that Olig2 was overexpressed in melanoma cells and tissues. Reduction of Olig2 increased apoptosis in melanoma cells by increasing p53 level and caspase-3/-7 enzyme activity. In addition, downregulation of Olig2 suppressed migration and invasion of melanoma cells by inhibiting EMT. Reduction of Olig2 inhibited expression of MMP-1 and the enzyme activity of MMP-2/-9 induced by TGF-β. Moreover, Olig2 was involved in the downstream stages of MEK/ERK and PI3K/AKT, which are major signaling pathways in metastatic progression of melanoma. In conclusion, this study demonstrated the crucial roles of Olig2 in apoptosis, migration, and invasion of melanoma and may help to further our understanding of the relationship between Olig2 and melanoma progression.

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EPCO-32. AN EPIGENETIC SINGLE-CELL ATLAS OF IDH-MUTANT GLIOMA REVEALS THE ROLE OF ATRX IN SHAPING TUMOR COMPOSITION

Neuro-Oncology ◽

10.1093/neuonc/noaa215.311 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii76-ii76

Author(s):

Husam Babikir ◽

Lin Wang ◽

Karin Shamardani ◽

Sweta Sudhir ◽

Gary Kohanbash ◽

...

Keyword(s):

Transcription Factor ◽

Single Cell ◽

Rna Sequencing ◽

Myeloid Cell ◽

Cell Types ◽

Open Chromatin ◽

Helix Loop Helix ◽

Local Immunosuppression ◽

Single Cell Rna Sequencing

Abstract Recent single-cell RNA-sequencing studies have identified a hierarchy of cell types that is common to all isocitrate dehydrogenase (IDH) -mutant gliomas. This finding is somewhat paradoxical since the genetic differences between IDH-mutant astrocytomas and IDH-mutant oligodendrogliomas are prognostic, predictive of therapeutic response, and correlated with differences in immune infiltrates. To integrate these disparate findings, we constructed a single-cell atlas of 28 human IDH-mutant primary untreated grade-II/III gliomas. All specimens were profiled by single-cell assay for transposase-accessible chromatin, with additional cohorts profiled via single-cell RNA-sequencing and single-cell spatial proteomics. We determined the cell-type specific differences between IDH-mutant gliomas in transcription-factor utilization, associated targeting and cis-regulatory grammars. To elucidate the role of the chromatin remodeler ATRX (inactivated in over 86% of IDH-mutant astrocytomas) in shaping observed differences in open chromatin, we knocked out ATRX in an immunocompetent model of IDH-mutant glioma and subjected murine tumors to single-cell profiling. We found: 1. ATRX-deficient, IDH-mutant human and murine gliomas both upregulate an astrocytic regulatory program driven by Nuclear Factor I genes and downregulate an oligodendrocytic program driven by basic helix-loop-helix transcription factors. 2. Both human and mouse ATRX-deficient, IDH-mutant gliomas up-regulate genes that promote myeloid-cell chemotaxis and both have significantly higher percentages of myeloid-derived immune-suppressive cells than controls; 3. A transcription-factor program is conserved between human and murine ATRX-deficient tumors that shapes glial identity and promotes local immunosuppression. These studies elucidate how IDH-mutant gliomas from different subtypes can have distinct cellular morphologies and tumor micronenvironments despite a common lineage hierarchy.

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Role of epithelial–mesenchymal transition regulated by twist basic helix-loop-helix transcription factor 2 (Twist2) in embryo implantation in mice

Reproduction Fertility and Development ◽

10.1071/rd18314 ◽

2019 ◽

Vol 31 (5) ◽

pp. 932

Author(s):

Jinhai Gou ◽

Tingwenyi Hu ◽

Lin Li ◽

Luqi Xue ◽

Xia Zhao ◽

...

Keyword(s):

Transcription Factor ◽

Western Blot ◽

Epithelial Mesenchymal Transition ◽

Embryo Implantation ◽

Mesenchymal Transition ◽

Basic Helix Loop Helix ◽

Helix Loop Helix ◽

Implantation Sites ◽

E Cadherin

In a previous study we found the expression of epithelial–mesenchymal transition (EMT) biomarkers, including E-cadherin and N-cadherin, was significantly altered in uterine endometrium during embryo implantation via regulation by microRNA (miRNA)-429 and protocadherin-8 (Pcdh8). As a natural continuation of the previous study, the aim of the present study was to explore the role of EMT during embryo implantation and the potential activity of twist basic helix-loop-helix transcription factor 2 (Twist2) in regulating embryo implantation. A pregnancy model was established by naturally mating adult female ICR mice with fertile males. A pseudopregnancy model was established by mating fertile female ICR mice with vasectomised males. An invitro model of embryo implantation was established by the coculture of Ishikawa and JAR spheroids. Endometrial tissue during the peri-implantation period was collected, as were Ishikawa cells, JAR cells and cocultured cells. The expression of EMT markers (E-cadherin, N-cadherin, vimentin and cytokeratin) and Twist2 was detected invivo and invitro using the western blot analysis during embryo implantation. The expression of N-cadherin and vimentin (mesenchymal markers) was upregulated in the invitro implantation model, with downregulation of E-cadherin and cytokeratin (epithelial markers) expression. The expression of N-cadherin, vimentin and Twist2 increased significantly at the implantation sites at the time of implantation (Day 5), whereas the expression of E-cadherin and cytokeratin decreased. Location of Twist2 during embryo implantation was detected by immunohistochemistry (IHC), which revealed that it was extensively expressed in endometrial glandular epithelium and luminal epithelium at implantation sites on Day 5. The effect of the expression of Twist2 on embryo implantation was evaluated by suppressing Twist2 using Twist2-short interference (si) RNA in invivo and invitro models. The numbers of implanted embryos and the implantation rate were compared invivo and invitro. Western blot analysis showed that suppression of Twist2 led to upregulation of E-cadherin and cytokeratin, accompanied by downregulation of N-cadherin and vimentin (P<0.05). The number of implanted embryos after Twist2-siRNA interference was lower than in normal pregnancy (mean (±s.d.) 2.4±0.5 vs 6.8±1.3 respectively; P<0.05). These findings suggest the involvement of EMT in embryo implantation. The suppression of Twist2 could suppress embryo implantation by regulating EMT.

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Transcription factor 4 and its association with psychiatric disorders

Translational Psychiatry ◽

10.1038/s41398-020-01138-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

José R. Teixeira ◽

Ryan A. Szeto ◽

Vinicius M. A. Carvalho ◽

Alysson R. Muotri ◽

Fabio Papes

Keyword(s):

Transcription Factor ◽

Neural Development ◽

Motor Development ◽

Autism Spectrum ◽

The Body ◽

Helix Loop Helix ◽

Severe Intellectual Disability ◽

Transcription Factor 4 ◽

Human Transcription Factor

AbstractThe human transcription factor 4 gene (TCF4) encodes a helix–loop–helix transcription factor widely expressed throughout the body and during neural development. Mutations in TCF4 cause a devastating autism spectrum disorder known as Pitt–Hopkins syndrome, characterized by a range of aberrant phenotypes including severe intellectual disability, absence of speech, delayed cognitive and motor development, and dysmorphic features. Moreover, polymorphisms in TCF4 have been associated with schizophrenia and other psychiatric and neurological conditions. Details about how TCF4 genetic variants are linked to these diseases and the role of TCF4 during neural development are only now beginning to emerge. Here, we provide a comprehensive review of the functions of TCF4 and its protein products at both the cellular and organismic levels, as well as a description of pathophysiological mechanisms associated with this gene.

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The Transcription Factor OVOL2 Represses ID2 and Drives Differentiation of Trophoblast Stem Cells and Placental Development in Mice

Cells ◽

10.3390/cells9040840 ◽

2020 ◽

Vol 9 (4) ◽

pp. 840 ◽

Cited By ~ 2

Author(s):

Mariyan J. Jeyarajah ◽

Gargi Jaju Bhattad ◽

Dendra M. Hillier ◽

Stephen J. Renaud

Keyword(s):

Transcription Factor ◽

Cell Differentiation ◽

Cell Fate ◽

Critical Role ◽

Dominant Negative ◽

Placental Development ◽

Differentiation Potential ◽

Helix Loop Helix ◽

Trophoblast Stem

Trophoblasts are the first cell type to be specified during embryogenesis, and they are essential for placental morphogenesis and function. Trophoblast stem (TS) cells are the progenitor cells for all trophoblast lineages; control of TS cell differentiation into distinct trophoblast subtypes is not well understood. Mice lacking the transcription factor OVO-like 2 (OVOL2) fail to produce a functioning placenta, and die around embryonic day 10.5, suggesting that OVOL2 may be critical for trophoblast development. Therefore, our objective was to determine the role of OVOL2 in mouse TS cell fate. We found that OVOL2 was highly expressed in mouse placenta and differentiating TS cells. Placentas and TS cells lacking OVOL2 showed poor trophoblast differentiation potential, including increased expression of stem-state associated genes (Eomes, Esrrb, Id2) and decreased levels of differentiation-associated transcripts (Gcm1, Tpbpa, Prl3b1, Syna). Ectopic OVOL2 expression in TS cells elicited precocious differentiation. OVOL2 bound proximate to the gene encoding inhibitor of differentiation 2 (ID2), a dominant negative helix-loop-helix protein, and directly repressed its activity. Overexpression of ID2 was sufficient to reinforce the TS cell stem state. Our findings reveal a critical role of OVOL2 as a regulator of TS cell differentiation and placental development, in-part by coordinating repression of ID2.

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