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Transcriptional Regulation and Its Misregulation in Human Diseases
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Transcriptional Regulation and Its Misregulation in Human Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 53819

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Amelia Casamassimi

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Guest Editor
Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
Interests: cancer; PRDM genes; transcriptional regulation
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Alfredo Ciccodicola

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Guest Editor
1. CNR, Institute of Genetics and Biophysics “Adriano Buzzati-Traverso”, Via Pietro Castellino, 111-80131 Naples, Italy
2. Department of Science and Technology, University of Naples “Parthenope", Centro Direzionale, Isola C4-800143, Naples, Italy
Interests: human genetic diseases; molecular mechanism pathogenesis; whole-transcriptome analysis; non-coding RNAs
Special Issues, Collections and Topics in MDPI journals
Dr. Monica Rienzo

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Guest Editor
Department of Environmental, Biological, and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
Interests: PRDM genes; cancer; transcriptional regulation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Transcriptional regulation is a critical biological process that allows the cell or an organism to respond to a variety of intra- and extracellular signals, to define cell identity during development, to maintain it throughout its lifetime, and to coordinate cellular activity. This control involves multiple temporal and functional steps as well as innumerable molecules including transcription factors, cofactors and chromatin regulators. It is well known that many human disorders are characterized by global transcriptional dysregulation because most of the signaling pathways ultimately target transcription machinery. Indeed, many syndromes and genetic and complex diseases—cancer, autoimmunity, neurological and developmental disorders, metabolic and cardiovascular diseases—can be caused by mutations/alterations in regulatory sequences, transcription factors, splicing regulators, cofactors, chromatin regulators, ncRNAs, and other components of transcription apparatus. It is worth noting that advances in our understanding of molecules and mechanisms involved in the transcriptional circuitry and apparatus lead to new insights into the pathogenetic mechanisms of various human diseases and disorders. Thus, this Special Issue is focused on molecular genetics and genomics studies exploring the effects of transcriptional misregulation on human diseases.

Dr. Amelia Casamassimi
Prof. Dr. Alfredo Ciccodicola
Dr. Monica Rienzo
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Transcription machinery
  • Transcription factors
  • Transcription cofactors and complexes
  • Chromatin regulators
  • Splicing regulators
  • Noncoding RNAs
  • Posttranscriptional modifications
  • Transcription misregulation
  • Genetic alterations
  • Human diseases

Published Papers (19 papers)

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Editorial

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7 pages, 232 KiB  
Editorial
Transcriptional Regulation and Its Misregulation in Human Diseases
by Amelia Casamassimi, Alfredo Ciccodicola and Monica Rienzo
Int. J. Mol. Sci. 2023, 24(10), 8640; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24108640 - 12 May 2023
Viewed by 963
Abstract
Transcriptional regulation is a critical biological process that allows the cell or an organism to respond to a variety of intra- and extracellular signals, to define cell identity during development, to maintain it throughout its lifetime, and to coordinate cellular activity [...] Full article
(This article belongs to the Special Issue Transcriptional Regulation and Its Misregulation in Human Diseases)

Research

Jump to: Editorial, Review

19 pages, 6740 KiB  
Article
The Hematopoietic TALE-Code Shows Normal Activity of IRX1 in Myeloid Progenitors and Reveals Ectopic Expression of IRX3 and IRX5 in Acute Myeloid Leukemia
by Stefan Nagel, Claudia Pommerenke, Corinna Meyer and Roderick A. F. MacLeod
Int. J. Mol. Sci. 2022, 23(6), 3192; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063192 - 16 Mar 2022
Cited by 9 | Viewed by 2337
Abstract
Homeobox genes encode transcription factors that control basic developmental decisions. Knowledge of their hematopoietic activities casts light on normal and malignant immune cell development. Recently, we constructed the so-called lymphoid TALE-code that codifies expression patterns of all active TALE class homeobox genes in [...] Read more.
Homeobox genes encode transcription factors that control basic developmental decisions. Knowledge of their hematopoietic activities casts light on normal and malignant immune cell development. Recently, we constructed the so-called lymphoid TALE-code that codifies expression patterns of all active TALE class homeobox genes in early hematopoiesis and lymphopoiesis. Here, we present the corresponding myeloid TALE-code to extend this gene signature, covering the entire hematopoietic system. The collective data showed expression patterns for eleven TALE homeobox genes and highlighted the exclusive expression of IRX1 in megakaryocyte-erythroid progenitors (MEPs), implicating this TALE class member in a specific myeloid differentiation process. Analysis of public profiling data from acute myeloid leukemia (AML) patients revealed aberrant activity of IRX1 in addition to IRX3 and IRX5, indicating an oncogenic role for these TALE homeobox genes when deregulated. Screening of RNA-seq data from 100 leukemia/lymphoma cell lines showed overexpression of IRX1, IRX3, and IRX5 in megakaryoblastic and myelomonocytic AML cell lines, chosen as suitable models for studying the regulation and function of these homeo-oncogenes. Genomic copy number analysis of IRX-positive cell lines demonstrated chromosomal amplification of the neighboring IRX3 and IRX5 genes at position 16q12 in MEGAL, underlying their overexpression in this cell line model. Comparative gene expression analysis of these cell lines revealed candidate upstream factors and target genes, namely the co-expression of GATA1 and GATA2 together with IRX1, and of BMP2 and HOXA10 with IRX3/IRX5. Subsequent knockdown and stimulation experiments in AML cell lines confirmed their activating impact in the corresponding IRX gene expression. Furthermore, we demonstrated that IRX1 activated KLF1 and TAL1, while IRX3 inhibited GATA1, GATA2, and FST. Accordingly, we propose that these regulatory relationships may represent major physiological and oncogenic activities of IRX factors in normal and malignant myeloid differentiation, respectively. Finally, the established myeloid TALE-code is a useful tool for evaluating TALE homeobox gene activities in AML. Full article
(This article belongs to the Special Issue Transcriptional Regulation and Its Misregulation in Human Diseases)
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14 pages, 1916 KiB  
Article
Transcriptional Alterations in X-Linked Dystonia–Parkinsonism Caused by the SVA Retrotransposon
by Jelena Pozojevic, Shela Marie Algodon, Joseph Neos Cruz, Joanne Trinh, Norbert Brüggemann, Joshua Laß, Karen Grütz, Susen Schaake, Ronnie Tse, Veronica Yumiceba, Nathalie Kruse, Kristin Schulz, Varun K. A. Sreenivasan, Raymond L. Rosales, Roland Dominic G. Jamora, Cid Czarina E. Diesta, Jakob Matschke, Markus Glatzel, Philip Seibler, Kristian Händler, Aleksandar Rakovic, Henriette Kirchner, Malte Spielmann, Frank J. Kaiser, Christine Klein and Ana Westenbergeradd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2022, 23(4), 2231; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042231 - 17 Feb 2022
Cited by 6 | Viewed by 2680
Abstract
X-linked dystonia–parkinsonism (XDP) is a severe neurodegenerative disorder that manifests as adult-onset dystonia combined with parkinsonism. A SINE-VNTR-Alu (SVA) retrotransposon inserted in an intron of the TAF1 gene reduces its expression and alters splicing in XDP patient-derived cells. As a consequence, increased levels [...] Read more.
X-linked dystonia–parkinsonism (XDP) is a severe neurodegenerative disorder that manifests as adult-onset dystonia combined with parkinsonism. A SINE-VNTR-Alu (SVA) retrotransposon inserted in an intron of the TAF1 gene reduces its expression and alters splicing in XDP patient-derived cells. As a consequence, increased levels of the TAF1 intron retention transcript TAF1-32i can be found in XDP cells as compared to healthy controls. Here, we investigate the sequence of the deep intronic region included in this transcript and show that it is also present in cells from healthy individuals, albeit in lower amounts than in XDP cells, and that it undergoes degradation by nonsense-mediated mRNA decay. Furthermore, we investigate epigenetic marks (e.g., DNA methylation and histone modifications) present in this intronic region and the spanning sequence. Finally, we show that the SVA evinces regulatory potential, as demonstrated by its ability to repress the TAF1 promoter in vitro. Our results enable a better understanding of the disease mechanisms underlying XDP and transcriptional alterations caused by SVA retrotransposons. Full article
(This article belongs to the Special Issue Transcriptional Regulation and Its Misregulation in Human Diseases)
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19 pages, 2642 KiB  
Article
Transcriptional Regulation of Yin-Yang 1 Expression through the Hypoxia Inducible Factor-1 in Pediatric Acute Lymphoblastic Leukemia
by Gabriela Antonio-Andres, Gustavo U. Martinez-Ruiz, Mario Morales-Martinez, Elva Jiménez-Hernandez, Estefany Martinez-Torres, Tania V. Lopez-Perez, Laura A. Estrada-Abreo, Genaro Patino-Lopez, Sergio Juarez-Mendez, Víctor M. Davila-Borja and Sara Huerta-Yepez
Int. J. Mol. Sci. 2022, 23(3), 1728; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031728 - 02 Feb 2022
Cited by 4 | Viewed by 2177
Abstract
Yin-Yang transcription factor 1 (YY1) is involved in tumor progression, metastasis and has been shown to be elevated in different cancers, including leukemia. The regulatory mechanism underlying YY1 expression in leukemia is still not understood. Bioinformatics analysis reveal three Hypoxia-inducible factor 1-alpha (HIF-1α) [...] Read more.
Yin-Yang transcription factor 1 (YY1) is involved in tumor progression, metastasis and has been shown to be elevated in different cancers, including leukemia. The regulatory mechanism underlying YY1 expression in leukemia is still not understood. Bioinformatics analysis reveal three Hypoxia-inducible factor 1-alpha (HIF-1α) putative binding sites in the YY1 promoter region. The regulation of YY1 by HIF-1α in leukemia was analyzed. Mutation of the putative YY1 binding sites in a reporter system containing the HIF-1α promoter region and CHIP analysis confirmed that these sites are important for YY1 regulation. Leukemia cell lines showed that both proteins HIF-1α and YY1 are co-expressed under hypoxia. In addition, the expression of mRNA of YY1 was increased after 3 h of hypoxia conditions and affect several target genes expression. In contrast, chemical inhibition of HIF-1α induces downregulation of YY1 and sensitizes cells to chemotherapeutic drugs. The clinical implications of HIF-1α in the regulation of YY1 were investigated by evaluation of expression of HIF-1α and YY1 in 108 peripheral blood samples and by RT-PCR in 46 bone marrow samples of patients with pediatric acute lymphoblastic leukemia (ALL). We found that the expression of HIF-1α positively correlates with YY1 expression in those patients. This is consistent with bioinformatic analyses of several databases. Our findings demonstrate for the first time that YY1 can be transcriptionally regulated by HIF-1α, and a correlation between HIF-1α expression and YY1 was found in ALL clinical samples. Hence, HIF-1α and YY1 may be possible therapeutic target and/or biomarkers of ALL. Full article
(This article belongs to the Special Issue Transcriptional Regulation and Its Misregulation in Human Diseases)
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17 pages, 2111 KiB  
Article
The QseEF Two-Component System-GlmY Small RNA Regulatory Pathway Controls Swarming in Uropathogenic Proteus mirabilis
by Wen-Yuan Lin, Yuan-Ju Lee, Ping-Hung Yu, Yi-Lin Tsai, Pin-Yi She, Tzung-Shian Li and Shwu-Jen Liaw
Int. J. Mol. Sci. 2022, 23(1), 487; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010487 - 01 Jan 2022
Cited by 6 | Viewed by 1830
Abstract
Bacterial sensing of environmental signals through the two-component system (TCS) plays a key role in modulating virulence. In the search for the host hormone-sensing TCS, we identified a conserved qseEGF locus following glmY, a small RNA (sRNA) gene in uropathogenic Proteus mirabilis [...] Read more.
Bacterial sensing of environmental signals through the two-component system (TCS) plays a key role in modulating virulence. In the search for the host hormone-sensing TCS, we identified a conserved qseEGF locus following glmY, a small RNA (sRNA) gene in uropathogenic Proteus mirabilis. Genes of glmY-qseE-qseG-qseF constitute an operon, and QseF binding sites were found in the glmY promoter region. Deletion of glmY or qseF resulted in reduced swarming motility and swarming-related phenotypes relative to the wild-type and the respective complemented strains. The qseF mutant had decreased glmYqseEGF promoter activity. Both glmY and qseF mutants exhibited decreased flhDC promoter activity and mRNA level, while increased rcsB mRNA level was observed in both mutants. Prediction by TargetRNA2 revealed cheA as the target of GlmY. Then, construction of the translational fusions containing various lengths of cheA 5′UTR for reporter assay and site-directed mutagenesis were performed to investigate the cheA-GlmY interaction in cheA activation. Notably, loss of glmY reduced the cheA mRNA level, and urea could inhibit swarming in a QseF-dependent manner. Altogether, this is the first report elucidating the underlying mechanisms for modulation of swarming motility by a QseEF-regulated sRNA GlmY, involving expression of cheA, rcsB and flhDC in uropathogenic P. mirabilis. Full article
(This article belongs to the Special Issue Transcriptional Regulation and Its Misregulation in Human Diseases)
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14 pages, 2665 KiB  
Article
Identification of Novel Micropeptides Derived from Hepatocellular Carcinoma-Specific Long Noncoding RNA
by Mareike Polenkowski, Sebastian Burbano de Lara, Aldrige Bernardus Allister, Thi Nhu Quynh Nguyen, Teruko Tamura and Doan Duy Hai Tran
Int. J. Mol. Sci. 2022, 23(1), 58; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010058 - 21 Dec 2021
Cited by 13 | Viewed by 3810
Abstract
Identification of cancer-specific target molecules and biomarkers may be useful in the development of novel treatment and immunotherapeutic strategies. We have recently demonstrated that the expression of long noncoding (lnc) RNAs can be cancer-type specific due to abnormal chromatin remodeling and alternative splicing. [...] Read more.
Identification of cancer-specific target molecules and biomarkers may be useful in the development of novel treatment and immunotherapeutic strategies. We have recently demonstrated that the expression of long noncoding (lnc) RNAs can be cancer-type specific due to abnormal chromatin remodeling and alternative splicing. Furthermore, we identified and determined that the functional small protein C20orf204-189AA encoded by long intergenic noncoding RNA Linc00176 that is expressed predominantly in hepatocellular carcinoma (HCC), enhances transcription of ribosomal RNAs and supports growth of HCC. In this study we combined RNA-sequencing and polysome profiling to identify novel micropeptides that originate from HCC-specific lncRNAs. We identified nine lncRNAs that are expressed exclusively in HCC cells but not in the liver or other normal tissues. Here, DNase-sequencing data revealed that the altered chromatin structure plays a key role in the HCC-specific expression of lncRNAs. Three out of nine HCC-specific lncRNAs contain at least one open reading frame (ORF) longer than 50 amino acid (aa) and enriched in the polysome fraction, suggesting that they are translated. We generated a peptide specific antibody to characterize one candidate, NONHSAT013026.2/Linc013026. We show that Linc013026 encodes a 68 amino acid micropeptide that is mainly localized at the perinuclear region. Linc013026-68AA is expressed in a subset of HCC cells and plays a role in cell proliferation, suggesting that Linc013026-68AA may be used as a HCC-specific target molecule. Our finding also sheds light on the role of the previously ignored ’dark proteome’, that originates from noncoding regions in the maintenance of cancer. Full article
(This article belongs to the Special Issue Transcriptional Regulation and Its Misregulation in Human Diseases)
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13 pages, 2886 KiB  
Article
Comparative Transcriptome Profiling of Young and Old Brown Adipose Tissue Thermogenesis
by Yumin Kim, Baeki E. Kang, Dongryeol Ryu, So Won Oh and Chang-Myung Oh
Int. J. Mol. Sci. 2021, 22(23), 13143; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222313143 - 05 Dec 2021
Cited by 8 | Viewed by 2450
Abstract
Brown adipose tissue (BAT) is a major site for uncoupling protein 1 (UCP1)-mediated non-shivering thermogenesis. BAT dissipates energy via heat generation to maintain the optimal body temperature and increases energy expenditure. These energetic processes in BAT use large amounts of glucose and fatty [...] Read more.
Brown adipose tissue (BAT) is a major site for uncoupling protein 1 (UCP1)-mediated non-shivering thermogenesis. BAT dissipates energy via heat generation to maintain the optimal body temperature and increases energy expenditure. These energetic processes in BAT use large amounts of glucose and fatty acid. Therefore, the thermogenesis of BAT may be harnessed to treat obesity and related diseases. In mice and humans, BAT levels decrease with aging, and the underlying mechanism is elusive. Here, we compared the transcriptomic profiles of both young and aged BAT in response to thermogenic stimuli. The profiles were extracted from the GEO database. Intriguingly, aging does not cause transcriptional changes in thermogenic genes but upregulates several pathways related to the immune response and downregulates metabolic pathways. Acute severe CE upregulates several pathways related to protein folding. Chronic mild CE upregulates metabolic pathways, especially related to carbohydrate metabolism. Our findings provide a better understanding of the effects of aging and metabolic responses to thermogenic stimuli in BAT at the transcriptome level. Full article
(This article belongs to the Special Issue Transcriptional Regulation and Its Misregulation in Human Diseases)
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17 pages, 1225 KiB  
Article
Ultrasensitive Detection of Bacillus anthracis by Real-Time PCR Targeting a Polymorphism in Multi-Copy 16S rRNA Genes and Their Transcripts
by Peter Braun, Martin Duy-Thanh Nguyen, Mathias C. Walter and Gregor Grass
Int. J. Mol. Sci. 2021, 22(22), 12224; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212224 - 12 Nov 2021
Cited by 11 | Viewed by 3248
Abstract
The anthrax pathogen Bacillus anthracis poses a significant threat to human health. Identification of B. anthracis is challenging because of the bacterium’s close genetic relationship to other Bacillus cereus group species. Thus, molecular detection is founded on species-specific PCR targeting single-copy genes. Here, [...] Read more.
The anthrax pathogen Bacillus anthracis poses a significant threat to human health. Identification of B. anthracis is challenging because of the bacterium’s close genetic relationship to other Bacillus cereus group species. Thus, molecular detection is founded on species-specific PCR targeting single-copy genes. Here, we validated a previously recognized multi-copy target, a species-specific single nucleotide polymorphism (SNP) present in 2–5 copies in every B. anthracis genome analyzed. For this, a hydrolysis probe-based real-time PCR assay was developed and rigorously tested. The assay was specific as only B. anthracis DNA yielded positive results, was linear over 9 log10 units, and was sensitive with a limit of detection (LoD) of 2.9 copies/reaction. Though not exhibiting a lower LoD than established single-copy PCR targets (dhp61 or PL3), the higher copy number of the B. anthracis–specific 16S rRNA gene alleles afforded ≤2 unit lower threshold (Ct) values. To push the detection limit even further, the assay was adapted for reverse transcription PCR on 16S rRNA transcripts. This RT-PCR assay was also linear over 9 log10 units and was sensitive with an LoD of 6.3 copies/reaction. In a dilution series of experiments, the 16S RT-PCR assay achieved a thousand-fold higher sensitivity than the DNA-targeting assays. For molecular diagnostics, we recommend a real-time RT-PCR assay variant in which both DNA and RNA serve as templates (thus, no requirement for DNase treatment). This can at least provide results equaling the DNA-based implementation if no RNA is present but is superior even at the lowest residual rRNA concentrations. Full article
(This article belongs to the Special Issue Transcriptional Regulation and Its Misregulation in Human Diseases)
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16 pages, 4175 KiB  
Article
The Fusion of CLEC12A and MIR223HG Arises from a trans-Splicing Event in Normal and Transformed Human Cells
by Bijay P. Dhungel, Geoffray Monteuuis, Caroline Giardina, Mehdi S. Tabar, Yue Feng, Cynthia Metierre, Sarah Ho, Rajini Nagarajah, Angela R. M. Fontaine, Jaynish S. Shah, Divya Gokal, Charles G. Bailey, Ulf Schmitz and John E. J. Rasko
Int. J. Mol. Sci. 2021, 22(22), 12178; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212178 - 10 Nov 2021
Cited by 5 | Viewed by 2739
Abstract
Chimeric RNAs are often associated with chromosomal rearrangements in cancer. In addition, they are also widely detected in normal tissues, contributing to transcriptomic complexity. Despite their prevalence, little is known about the characteristics and functions of chimeric RNAs. Here, we examine the genetic [...] Read more.
Chimeric RNAs are often associated with chromosomal rearrangements in cancer. In addition, they are also widely detected in normal tissues, contributing to transcriptomic complexity. Despite their prevalence, little is known about the characteristics and functions of chimeric RNAs. Here, we examine the genetic structure and biological roles of CLEC12A-MIR223HG, a novel chimeric transcript produced by the fusion of the cell surface receptor CLEC12A and the miRNA-223 host gene (MIR223HG), first identified in chronic myeloid leukemia (CML) patients. Surprisingly, we observed that CLEC12A-MIR223HG is not just expressed in CML, but also in a variety of normal tissues and cell lines. CLEC12A-MIR223HG expression is elevated in pro-monocytic cells resistant to chemotherapy and during monocyte-to-macrophage differentiation. We observed that CLEC12A-MIR223HG is a product of trans-splicing rather than a chromosomal rearrangement and that transcriptional activation of CLEC12A with the CRISPR/Cas9 Synergistic Activation Mediator (SAM) system increases CLEC12A-MIR223HG expression. CLEC12A-MIR223HG translates into a chimeric protein, which largely resembles CLEC12A but harbours an altered C-type lectin domain altering key disulphide bonds. These alterations result in differences in post-translational modifications, cellular localization, and protein–protein interactions. Taken together, our observations support a possible involvement of CLEC12A-MIR223HG in the regulation of CLEC12A function. Our workflow also serves as a template to study other uncharacterized chimeric RNAs. Full article
(This article belongs to the Special Issue Transcriptional Regulation and Its Misregulation in Human Diseases)
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18 pages, 3888 KiB  
Article
NKL Homeobox Genes NKX2-3 and NKX2-4 Deregulate Megakaryocytic-Erythroid Cell Differentiation in AML
by Stefan Nagel, Claudia Pommerenke, Corinna Meyer and Roderick A. F. MacLeod
Int. J. Mol. Sci. 2021, 22(21), 11434; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111434 - 22 Oct 2021
Cited by 8 | Viewed by 2229
Abstract
NKL homeobox genes encode transcription factors that impact normal development and hematopoietic malignancies if deregulated. Recently, we established an NKL-code that describes the physiological expression pattern of eleven NKL homeobox genes in the course of hematopoiesis, allowing evaluation of aberrantly activated NKL genes [...] Read more.
NKL homeobox genes encode transcription factors that impact normal development and hematopoietic malignancies if deregulated. Recently, we established an NKL-code that describes the physiological expression pattern of eleven NKL homeobox genes in the course of hematopoiesis, allowing evaluation of aberrantly activated NKL genes in leukemia/lymphoma. Here, we identify ectopic expression of NKL homeobox gene NKX2-4 in an erythroblastic acute myeloid leukemia (AML) cell line OCI-M2 and describe investigation of its activating factors and target genes. Comparative expression profiling data of AML cell lines revealed in OCI-M2 an aberrantly activated program for endothelial development including master factor ETV2 and the additional endothelial signature genes HEY1, IRF6, and SOX7. Corresponding siRNA-mediated knockdown experiments showed their role in activating NKX2-4 expression. Furthermore, the ETV2 locus at 19p13 was genomically amplified, possibly underlying its aberrant expression. Target gene analyses of NKX2-4 revealed activated ETV2, HEY1, and SIX5 and suppressed FLI1. Comparative expression profiling analysis of public datasets for AML patients and primary megakaryocyte–erythroid progenitor cells showed conspicuous similarities to NKX2-4 activating factors and the target genes we identified, supporting the clinical relevance of our findings and developmental disturbance by NKX2-4. Finally, identification and target gene analysis of aberrantly expressed NKX2-3 in AML patients and a megakaryoblastic AML cell line ELF-153 showed activation of FLI1, contrasting with OCI-M2. FLI1 encodes a master factor for myelopoiesis, driving megakaryocytic differentiation and suppressing erythroid differentiation, thus representing a basic developmental target of these homeo-oncogenes. Taken together, we have identified aberrantly activated NKL homeobox genes NKX2-3 and NKX2-4 in AML, deregulating genes involved in megakaryocytic and erythroid differentiation processes, and thereby contributing to the formation of specific AML subtypes. Full article
(This article belongs to the Special Issue Transcriptional Regulation and Its Misregulation in Human Diseases)
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13 pages, 1101 KiB  
Article
Forkhead Box Protein P3 (FOXP3) Represses ATF3 Transcriptional Activity
by Chiung-Min Wang, William Harry Yang, Leticia Cardoso, Ninoska Gutierrez, Richard Henry Yang and Wei-Hsiung Yang
Int. J. Mol. Sci. 2021, 22(21), 11400; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111400 - 22 Oct 2021
Cited by 8 | Viewed by 2342
Abstract
Activating transcription factor 3 (ATF3), a transcription factor and acute stress sensor, is rapidly induced by a variety of pathophysiological signals and is essential in the complex processes in cellular stress response. FOXP3, a well-known breast and prostate tumor suppressor from the X [...] Read more.
Activating transcription factor 3 (ATF3), a transcription factor and acute stress sensor, is rapidly induced by a variety of pathophysiological signals and is essential in the complex processes in cellular stress response. FOXP3, a well-known breast and prostate tumor suppressor from the X chromosome, is a novel transcriptional repressor for several oncogenes. However, it remains unknown whether ATF3 is the target protein of FOXP3. Herein, we demonstrate that ATF3 expression is regulated by FOXP3. Firstly, we observed that overexpression of FOXP3 reduced ATF3 protein level. Moreover, knockdown FOXP3 by siRNA increased ATF3 expression. Secondly, FOXP3 dose-dependently reduced ATF3 promoter activity in the luciferase reporter assay. Since FOXP3 is regulated by post-translational modifications (PTMs), we next investigated whether PTMs affect FOXP3-mediated ATF3 expression. Interestingly, we observed that phosphorylation mutation on FOXP3 (Y342F) significantly abolished FOXP3-mediated ATF3 expression. However, other PTM mutations on FOXP3, including S418 phosphorylation, K263 acetylation and ubiquitination, and K268 acetylation and ubiquitination, did not alter FOXP3-mediated ATF3 expression. Finally, the FOXP3 binding site was found on ATF3 promoter region by deletion and mutagenesis analysis. Taken together, our results suggest that FOXP3 functions as a novel regulator of ATF3 and that this novel event may be involved in tumor development and progression. Full article
(This article belongs to the Special Issue Transcriptional Regulation and Its Misregulation in Human Diseases)
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18 pages, 6321 KiB  
Article
Transcriptomic Profiling of Adult-Onset Asthma Related to Damp and Moldy Buildings and Idiopathic Environmental Intolerance
by Hille Suojalehto, Joseph Ndika, Irmeli Lindström, Liisa Airaksinen, Kirsi Karvala, Paula Kauppi, Antti Lauerma, Sanna Toppila-Salmi, Piia Karisola and Harri Alenius
Int. J. Mol. Sci. 2021, 22(19), 10679; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910679 - 01 Oct 2021
Cited by 4 | Viewed by 2977
Abstract
A subset of adult-onset asthma patients attribute their symptoms to damp and moldy buildings. Symptoms of idiopathic environmental intolerance (IEI) may resemble asthma and these two entities overlap. We aimed to evaluate if a distinct clinical subtype of asthma related to damp and [...] Read more.
A subset of adult-onset asthma patients attribute their symptoms to damp and moldy buildings. Symptoms of idiopathic environmental intolerance (IEI) may resemble asthma and these two entities overlap. We aimed to evaluate if a distinct clinical subtype of asthma related to damp and moldy buildings can be identified, to unravel its corresponding pathomechanistic gene signatures, and to investigate potential molecular similarities with IEI. Fifty female adult-onset asthma patients were categorized based on exposure to building dampness and molds during disease initiation. IEI patients (n = 17) and healthy subjects (n = 21) were also included yielding 88 study subjects. IEI was scored with the Quick Environmental Exposure and Sensitivity Inventory (QEESI) questionnaire. Inflammation was evaluated by blood cell type profiling and cytokine measurements. Disease mechanisms were investigated via gene set variation analysis of RNA from nasal biopsies and peripheral blood mononuclear cells. Nasal biopsy gene expression and plasma cytokine profiles suggested airway and systemic inflammation in asthma without exposure to dampness (AND). Similar evidence of inflammation was absent in patients with dampness-and-mold-related asthma (AAD). Gene expression signatures revealed a greater degree of similarity between IEI and dampness-related asthma than between IEI patients and asthma not associated to dampness and mold. Blood cell transcriptome of IEI subjects showed strong suppression of immune cell activation, migration, and movement. QEESI scores correlated to blood cell gene expression of all study subjects. Transcriptomic analysis revealed clear pathomechanisms for AND but not AAD patients. Furthermore, we found a distinct molecular pathological profile in nasal and blood immune cells of IEI subjects, including several differentially expressed genes that were also identified in AAD samples, suggesting IEI-type mechanisms. Full article
(This article belongs to the Special Issue Transcriptional Regulation and Its Misregulation in Human Diseases)
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12 pages, 1108 KiB  
Article
Epigenetic Biomarkers of Transition from Metabolically Healthy Obesity to Metabolically Unhealthy Obesity Phenotype: A Prospective Study
by Carolina Gutiérrez-Repiso, Teresa María Linares-Pineda, Andres Gonzalez-Jimenez, Francisca Aguilar-Lineros, Sergio Valdés, Federico Soriguer, Gemma Rojo-Martínez, Francisco J. Tinahones and Sonsoles Morcillo
Int. J. Mol. Sci. 2021, 22(19), 10417; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910417 - 27 Sep 2021
Cited by 9 | Viewed by 2911
Abstract
Background: Identifying those parameters that could potentially predict the deterioration of metabolically healthy phenotype is a matter of debate. In this field, epigenetics, in particular DNA methylation deserves special attention. Results: The aim of the present study was to analyze the long-term evolution [...] Read more.
Background: Identifying those parameters that could potentially predict the deterioration of metabolically healthy phenotype is a matter of debate. In this field, epigenetics, in particular DNA methylation deserves special attention. Results: The aim of the present study was to analyze the long-term evolution of methylation patterns in a subset of metabolically healthy subjects in order to search for epigenetic markers that could predict the progression to an unhealthy state. Twenty-six CpG sites were significantly differentially methylated, both at baseline and 11-year follow-up. These sites were related to 19 genes or pseudogenes; a more in-depth analysis of the methylation sites of these genes showed that CYP2E1 had 50% of the collected CpG sites differently methylated between stable metabolically healthy obesity (MHO) and unstable MHO, followed by HLA-DRB1 (33%), ZBTB45 (16%), HOOK3 (14%), PLCZ1 (14%), SLC1A1 (12%), MUC2 (12%), ZFPM2 (12.5%) and HLA-DQB2 (8%). Pathway analysis of the selected 26 CpG sites showed enrichment in pathways linked to th1 and th2 activation, antigen presentation, allograft rejection signals and metabolic processes. Higher methylation levels in the cg20707527 (ZFPM2) could have a protective effect against the progression to unstable MHO (OR: 0.21, 95%CI (0.067–0.667), p < 0.0001), whilst higher methylation levels in cg11445109 (CYP2E1) would increase the progression to MUO; OR: 2.72, 95%CI (1.094–6.796), p < 0.0014; respectively). Conclusions: DNA methylation status is associated with the stability/worsening of MHO phenotype. Two potential biomarkers of the transition to an unhealthy state were identified and deserve further investigation (cg20707527 and cg11445109). Moreover, the described differences in methylation could alter immune system-related pathways, highlighting these pathways as therapeutic targets to prevent metabolic deterioration in MHO patients. Full article
(This article belongs to the Special Issue Transcriptional Regulation and Its Misregulation in Human Diseases)
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20 pages, 29989 KiB  
Article
Parallel Reporter Assays Identify Altered Regulatory Role of rs684232 in Leading to Prostate Cancer Predisposition
by Naixia Ren, Qingqing Liu, Lingjie Yan and Qilai Huang
Int. J. Mol. Sci. 2021, 22(16), 8792; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168792 - 16 Aug 2021
Cited by 9 | Viewed by 2442
Abstract
Functional characterization of cancer risk-associated single nucleotide polymorphism (SNP) identified by genome-wide association studies (GWAS) has become a big challenge. To identify the regulatory risk SNPs that can lead to transcriptional misregulation, we performed parallel reporter gene assays with both alleles of 213 [...] Read more.
Functional characterization of cancer risk-associated single nucleotide polymorphism (SNP) identified by genome-wide association studies (GWAS) has become a big challenge. To identify the regulatory risk SNPs that can lead to transcriptional misregulation, we performed parallel reporter gene assays with both alleles of 213 prostate cancer risk-associated GWAS SNPs in 22Rv1 cells. We disclosed 32 regulatory SNPs that exhibited different regulatory activities with two alleles. For one of the regulatory SNPs, rs684232, we found that the variation altered chromatin binding of transcription factor FOXA1 on the DNA region and led to aberrant gene expression of VPS53, FAM57A, and GEMIN4, which play vital roles in prostate cancer malignancy. Our findings reveal the roles and underlying mechanism of rs684232 in prostate cancer progression and hold great promise in benefiting prostate cancer patients with prognostic prediction and target therapies. Full article
(This article belongs to the Special Issue Transcriptional Regulation and Its Misregulation in Human Diseases)
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Review

Jump to: Editorial, Research

20 pages, 867 KiB  
Review
Transcriptional Regulation of Endogenous Retroviruses and Their Misregulation in Human Diseases
by Qian Zhang, Juan Pan, Yusheng Cong and Jian Mao
Int. J. Mol. Sci. 2022, 23(17), 10112; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231710112 - 04 Sep 2022
Cited by 9 | Viewed by 3186
Abstract
Endogenous retroviruses (ERVs), deriving from exogenous retroviral infections of germ line cells occurred millions of years ago, represent ~8% of human genome. Most ERVs are highly inactivated because of the accumulation of mutations, insertions, deletions, and/or truncations. However, it is becoming increasingly apparent [...] Read more.
Endogenous retroviruses (ERVs), deriving from exogenous retroviral infections of germ line cells occurred millions of years ago, represent ~8% of human genome. Most ERVs are highly inactivated because of the accumulation of mutations, insertions, deletions, and/or truncations. However, it is becoming increasingly apparent that ERVs influence host biology through genetic and epigenetic mechanisms under particular physiological and pathological conditions, which provide both beneficial and deleterious effects for the host. For instance, certain ERVs expression is essential for human embryonic development. Whereas abnormal activation of ERVs was found to be involved in numbers of human diseases, such as cancer and neurodegenerative diseases. Therefore, understanding the mechanisms of regulation of ERVs would provide insights into the role of ERVs in health and diseases. Here, we provide an overview of mechanisms of transcriptional regulation of ERVs and their dysregulation in human diseases. Full article
(This article belongs to the Special Issue Transcriptional Regulation and Its Misregulation in Human Diseases)
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12 pages, 1836 KiB  
Review
Nuclear mRNA Export and Aging
by Hyun-Sun Park, Jongbok Lee, Hyun-Shik Lee, Seong Hoon Ahn and Hong-Yeoul Ryu
Int. J. Mol. Sci. 2022, 23(10), 5451; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105451 - 13 May 2022
Cited by 7 | Viewed by 2936
Abstract
The relationship between transcription and aging is one that has been studied intensively and experimentally with diverse attempts. However, the impact of the nuclear mRNA export on the aging process following its transcription is still poorly understood, although the nuclear events after transcription [...] Read more.
The relationship between transcription and aging is one that has been studied intensively and experimentally with diverse attempts. However, the impact of the nuclear mRNA export on the aging process following its transcription is still poorly understood, although the nuclear events after transcription are coupled closely with the transcription pathway because the essential factors required for mRNA transport, namely TREX, TREX-2, and nuclear pore complex (NPC), physically and functionally interact with various transcription factors, including the activator/repressor and pre-mRNA processing factors. Dysregulation of the mediating factors for mRNA export from the nucleus generally leads to the aberrant accumulation of nuclear mRNA and further impairment in the vegetative growth and normal lifespan and the pathogenesis of neurodegenerative diseases. The optimal stoichiometry and density of NPC are destroyed during the process of cellular aging, and their damage triggers a defect of function in the nuclear permeability barrier. This review describes recent findings regarding the role of the nuclear mRNA export in cellular aging and age-related neurodegenerative disorders. Full article
(This article belongs to the Special Issue Transcriptional Regulation and Its Misregulation in Human Diseases)
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16 pages, 1167 KiB  
Review
Molecular Pathways Modulating Sensory Hair Cell Regeneration in Adult Mammalian Cochleae: Progress and Perspectives
by Vikrant Rai, Shu Tu, Joseph R. Frank and Jian Zuo
Int. J. Mol. Sci. 2022, 23(1), 66; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010066 - 22 Dec 2021
Cited by 5 | Viewed by 3717
Abstract
Noise-induced, drug-related, and age-related disabling hearing loss is a major public health problem and affect approximately 466 million people worldwide. In non-mammalian vertebrates, the death of sensory hair cells (HCs) induces the proliferation and transdifferentiation of adjacent supporting cells into new HCs; however, [...] Read more.
Noise-induced, drug-related, and age-related disabling hearing loss is a major public health problem and affect approximately 466 million people worldwide. In non-mammalian vertebrates, the death of sensory hair cells (HCs) induces the proliferation and transdifferentiation of adjacent supporting cells into new HCs; however, this capacity is lost in juvenile and adult mammalian cochleae leading to permanent hearing loss. At present, cochlear implants and hearing devices are the only available treatments and can help patients to a certain extent; however, no biological approach or FDA-approved drug is effective to treat disabling hearing loss and restore hearing. Recently, regeneration of mammalian cochlear HCs by modulating molecular pathways or transcription factors has offered some promising results, although the immaturity of the regenerated HCs remains the biggest concern. Furthermore, most of the research done is in neonates and not in adults. This review focuses on critically summarizing the studies done in adult mammalian cochleae and discusses various strategies to elucidate novel transcription factors for better therapeutics. Full article
(This article belongs to the Special Issue Transcriptional Regulation and Its Misregulation in Human Diseases)
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10 pages, 1072 KiB  
Review
Pathophysiological Potentials of NRF3-Regulated Transcriptional Axes in Protein and Lipid Homeostasis
by Tsuyoshi Waku and Akira Kobayashi
Int. J. Mol. Sci. 2021, 22(23), 12686; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312686 - 24 Nov 2021
Cited by 5 | Viewed by 2936
Abstract
NRF3 (NFE2L3) belongs to the CNC-basic leucine zipper transcription factor family. An NRF3 homolog, NRF1 (NFE2L1), induces the expression of proteasome-related genes in response to proteasome inhibition. Another homolog, NRF2 (NFE2L2), induces the expression of genes related to antioxidant responses and encodes metabolic [...] Read more.
NRF3 (NFE2L3) belongs to the CNC-basic leucine zipper transcription factor family. An NRF3 homolog, NRF1 (NFE2L1), induces the expression of proteasome-related genes in response to proteasome inhibition. Another homolog, NRF2 (NFE2L2), induces the expression of genes related to antioxidant responses and encodes metabolic enzymes in response to oxidative stress. Dysfunction of each homolog causes several diseases, such as neurodegenerative diseases and cancer development. However, NRF3 target genes and their biological roles remain unknown. This review summarizes our recent reports that showed NRF3-regulated transcriptional axes for protein and lipid homeostasis. NRF3 induces the gene expression of POMP for 20S proteasome assembly and CPEB3 for NRF1 translational repression, inhibiting tumor suppression responses, including cell-cycle arrest and apoptosis, with resistance to a proteasome inhibitor anticancer agent bortezomib. NRF3 also promotes mevalonate biosynthesis by inducing SREBP2 and HMGCR gene expression, and reduces the intracellular levels of neural fatty acids by inducing GGPS1 gene expression. In parallel, NRF3 induces macropinocytosis for cholesterol uptake by inducing RAB5 gene expression. Finally, this review mentions not only the pathophysiological aspects of these NRF3-regulated axes for cancer cell growth and anti-obesity potential but also their possible role in obesity-induced cancer development. Full article
(This article belongs to the Special Issue Transcriptional Regulation and Its Misregulation in Human Diseases)
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14 pages, 908 KiB  
Review
Epigenetic Regulation and Post-Translational Modifications of SNAI1 in Cancer Metastasis
by Bo Dong and Yadi Wu
Int. J. Mol. Sci. 2021, 22(20), 11062; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011062 - 14 Oct 2021
Cited by 21 | Viewed by 3357
Abstract
SNAI1, a zinc finger transcription factor, not only acts as the master regulator of epithelial-mesenchymal transition (EMT) but also functions as a driver of cancer progression, including cell invasion, survival, immune regulation, stem cell properties, and metabolic regulation. The regulation of SNAI1 occurs [...] Read more.
SNAI1, a zinc finger transcription factor, not only acts as the master regulator of epithelial-mesenchymal transition (EMT) but also functions as a driver of cancer progression, including cell invasion, survival, immune regulation, stem cell properties, and metabolic regulation. The regulation of SNAI1 occurs at the transcriptional, translational, and predominant post-translational levels including phosphorylation, acetylation, and ubiquitination. Here, we discuss the regulation and role of SNAI1 in cancer metastasis, with a particular emphasis on epigenetic regulation and post-translational modifications. Understanding how signaling networks integrate with SNAI1 in cancer progression will shed new light on the mechanism of tumor metastasis and help develop novel therapeutic strategies against cancer metastasis. Full article
(This article belongs to the Special Issue Transcriptional Regulation and Its Misregulation in Human Diseases)
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