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Transcriptional Regulatory Mechanisms in Health and Disease

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell and Gene Therapy".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 19309

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Special Issue Editor

Prof. Dr. Mojgan Rastegar

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Guest Editor

Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
Interests: epigenetics; DNA methylation; transcriptional control; gene regulation; drug repurposing; neural stem cells; neurodevelopmental disorders; medulloblastoma brain tumor
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Gene regulatory mechanisms determine the expression state of each gene in a cell-type-specific and organ-dependent manner that are tightly controlled during development. Such regulatory mechanisms can act at the level of transcription, post-transcription, translation, and post-translation. Transcriptional regulation includes certain epigenetic mechanisms involving methylation and modification of DNA and RNA molecules, histone PTMs, action of non-coding RNAs, chromatin remodeling, nucleosome positioning, as well as interaction of trans-acting factors with cis-regulatory elements.

Transcriptional control is important for the proper process of embryonic development, organogenesis, and stem cell differentiation, with key roles in keeping our body in a health state. Accordingly, mis-regulation of transcriptional gene regulation leads to human disease.

The aim of this Special Issue is to serve as an overview platform for the latest discoveries in transcriptional gene regulation in development and disease, covering both original research and review articles. Post-transcriptional studies that involve the mechanistic basis of transcript turnover and/or transcript stability are also welcome. Studies that connect cellular function and signaling molecules to transcriptional gene regulation in development, health, and disease, as well as studies that report on the generation of novel model systems for transcriptional reporter assays are also welcome for submission.

Prof. Dr. Mojgan Rastegar
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

transcriptional regulation
chromatin remodeling
epigenetic modifications
cis-regulatory elements
trans-acting factors
nucleosome positioning
DNA–protein complexes
health and disease

Published Papers (5 papers)

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Research

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20 pages, 2518 KiB

Open AccessArticle

Bioinformatic Analyses of Broad H3K79me2 Domains in Different Leukemia Cell Line Data Sets

by Prerna Sharma, Hedieh Sattarifard, Narges Fatemiyan, Ted M. Lakowski and James R. Davie

Cells 2022, 11(18), 2830; https://doi.org/10.3390/cells11182830 - 10 Sep 2022

Cited by 6 | Viewed by 2430

Abstract

A subset of expressed genes is associated with a broad H3K4me3 (histone H3 trimethylated at lysine 4) domain that extends throughout the gene body. Genes marked in this way in normal cells are involved in cell-identity and tumor-suppressor activities, whereas in cancer cells, genes driving the cancer phenotype (oncogenes) have this feature. Other histone modifications associated with expressed genes that display a broad domain have been less studied. Here, we identified genes with the broadest H3K79me2 (histone H3 dimethylated at lysine 79) domain in human leukemic cell lines representing different forms of leukemia. Taking a bioinformatic approach, we provide evidence that genes with the broadest H3K79me2 domain have known roles in leukemia (e.g., JMJD1C). In the mixed-lineage leukemia cell line MOLM-13, the HOXA9 gene is in a 100 kb broad H3K79me2 domain with other HOXA protein-coding and oncogenic long non-coding RNA genes. The genes in this domain contribute to leukemia. This broad H3K79me2 domain has an unstable chromatin structure, as was evident by enhanced chromatin accessibility throughout. Together, we provide evidence that identification of genes with the broadest H3K79me2 domain will aid in generating a panel of genes in the diagnosis and therapeutic treatment of leukemia in the future. Full article

(This article belongs to the Special Issue Transcriptional Regulatory Mechanisms in Health and Disease)

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32 pages, 6691 KiB

Open AccessArticle

Differential Sensitivity of the Protein Translation Initiation Machinery and mTOR Signaling to MECP2 Gain- and Loss-of-Function Involves MeCP2 Isoform-Specific Homeostasis in the Brain

by Marjorie Buist, Nada El Tobgy, Danilo Shevkoplyas, Matthew Genung, Annan Ali Sher, Shervin Pejhan and Mojgan Rastegar

Cells 2022, 11(9), 1442; https://doi.org/10.3390/cells11091442 - 24 Apr 2022

Cited by 9 | Viewed by 2766

Abstract

Eukaryotic gene expression is controlled at multiple levels, including gene transcription and protein translation initiation. One molecule with key roles in both regulatory mechanisms is methyl CpG binding protein 2 (MeCP2). MECP2 gain- and loss-of-function mutations lead to Rett Syndrome and MECP2 Duplication Syndrome, respectively. To study MECP2 gain-of-function, we generated stably transduced human brain cells using lentiviral vectors for both MECP2E1 and MECP2E2 isoforms. Stable overexpression was confirmed by Western blot and immunofluorescence. We assessed the impact of MeCP2E1-E2 gain-of-function on the MeCP2 homeostasis regulatory network (MECP2E1/E2-BDNF/BDNF-miR-132), mTOR-AKT signaling, ribosome biogenesis, markers of chromatin structure, and protein translation initiation. We observed that combined co-transduction of MeCP2 isoforms led to protein degradation of MeCP2E1. Proteosome inhibition by MG132 treatment recovered MeCP2E1 protein within an hour, suggesting its induced degradation through the proteosome pathway. No significant change was detected for translation initiation factors as a result of MeCP2E1, MeCP2E2, or combined overexpression of both isoforms. In contrast, analysis of human Rett Syndrome brains tissues compared with controls indicated impaired protein translation initiation, suggesting that such mechanisms may have differential sensitivity to MECP2 gain- and loss-of-function. Collectively, our results provide further insight towards the dose-dependent functional role of MeCP2 isoforms in the human brain. Full article

(This article belongs to the Special Issue Transcriptional Regulatory Mechanisms in Health and Disease)

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Review

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21 pages, 1496 KiB

Open AccessReview

Histone Mono-Ubiquitination in Transcriptional Regulation and Its Mark on Life: Emerging Roles in Tissue Development and Disease

by Liat Oss-Ronen, Tzlil Sarusi and Idan Cohen

Cells 2022, 11(15), 2404; https://doi.org/10.3390/cells11152404 - 04 Aug 2022

Cited by 14 | Viewed by 5144

Abstract

Epigenetic regulation plays an essential role in driving precise transcriptional programs during development and homeostasis. Among epigenetic mechanisms, histone mono-ubiquitination has emerged as an important post-transcriptional modification. Two major histone mono-ubiquitination events are the mono-ubiquitination of histone H2A at lysine 119 (H2AK119ub), placed by Polycomb repressive complex 1 (PRC1), and histone H2B lysine 120 mono-ubiquitination (H2BK120ub), placed by the heteromeric RNF20/RNF40 complex. Both of these events play fundamental roles in shaping the chromatin epigenetic landscape and cellular identity. In this review we summarize the current understandings of molecular concepts behind histone mono-ubiquitination, focusing on their recently identified roles in tissue development and pathologies. Full article

(This article belongs to the Special Issue Transcriptional Regulatory Mechanisms in Health and Disease)

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16 pages, 1073 KiB

Open AccessFeature PaperReview

GLIS1-3: Links to Primary Cilium, Reprogramming, Stem Cell Renewal, and Disease

by Anton M. Jetten, David W. Scoville and Hong Soon Kang

Cells 2022, 11(11), 1833; https://doi.org/10.3390/cells11111833 - 03 Jun 2022

Cited by 3 | Viewed by 3379

Abstract

The GLI-Similar 1-3 (GLIS1-3) genes, in addition to encoding GLIS1-3 Krüppel-like zinc finger transcription factors, also generate circular GLIS (circGLIS) RNAs. GLIS1-3 regulate gene transcription by binding to GLIS binding sites in target genes, whereas circGLIS RNAs largely act as miRNA sponges. GLIS1-3 play a critical role in the regulation of many biological processes and have been implicated in various pathologies. GLIS protein activities appear to be regulated by primary cilium-dependent and -independent signaling pathways that via post-translational modifications may cause changes in the subcellular localization, proteolytic processing, and protein interactions. These modifications can affect the transcriptional activity of GLIS proteins and, consequently, the biological functions they regulate as well as their roles in disease. Recent studies have implicated GLIS1-3 proteins and circGLIS RNAs in the regulation of stemness, self-renewal, epithelial-mesenchymal transition (EMT), cell reprogramming, lineage determination, and differentiation. These biological processes are interconnected and play a critical role in embryonic development, tissue homeostasis, and cell plasticity. Dysregulation of these processes are part of many pathologies. This review provides an update on our current knowledge of the roles GLIS proteins and circGLIS RNAs in the control of these biological processes in relation to their regulation of normal physiological functions and disease. Full article

(This article belongs to the Special Issue Transcriptional Regulatory Mechanisms in Health and Disease)

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17 pages, 7065 KiB

Open AccessFeature PaperReview

The Role of MeCP2 in Regulating Synaptic Plasticity in the Context of Stress and Depression

by Carla L. Sánchez-Lafuente, Lisa E. Kalynchuk, Hector J. Caruncho and Juan Ausió

Cells 2022, 11(4), 748; https://doi.org/10.3390/cells11040748 - 21 Feb 2022

Cited by 13 | Viewed by 4385

Abstract

Methyl-CpG-binding protein 2 (MeCP2) is a transcriptional regulator that is highly abundant in the brain. It binds to methylated genomic DNA to regulate a range of physiological functions implicated in neuronal development and adult synaptic plasticity. MeCP2 has mainly been studied for its role in neurodevelopmental disorders, but alterations in MeCP2 are also present in stress-related disorders such as major depression. Impairments in both stress regulation and synaptic plasticity are associated with depression, but the specific mechanisms underlying these changes have not been identified. Here, we review the interplay between stress, synaptic plasticity, and MeCP2. We focus our attention on the transcriptional regulation of important neuronal plasticity genes such as BDNF and reelin (RELN). Moreover, we provide evidence from recent studies showing a link between chronic stress-induced depressive symptoms and dysregulation of MeCP2 expression, underscoring the role of this protein in stress-related pathology. We conclude that MeCP2 is a promising target for the development of novel, more efficacious therapeutics for the treatment of stress-related disorders such as depression. Full article

(This article belongs to the Special Issue Transcriptional Regulatory Mechanisms in Health and Disease)

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