Hepatic Nuclear Factor 1 Alpha (HNF-1α) In Human Physiology and Molecular Medicine

The transcription factors (TFs) play a crucial role in the modulation of specific gene transcription networks. One of the hepatocyte nuclear factors (HNFs) family’s member, hepatocyte nuclear factor-1α (HNF-1α) has continuously become a principal TF to control the expression of genes. It is involved in the regulation of a variety of functions in various human organs including liver, pancreas, intestine, and kidney. It regulates the expression of enzymes involved in endocrine and xenobiotic activity through various metabolite transporters located in the above organs. Its expression is also required for organ-specific cell fate determination. Despite two decades of its first identification in hepatocytes, a review of its significance was not comprehended. Here, the role of HNF-1α in the above organs at the molecular level to intimate molecular mechanisms for regulating certain gene expression whose malfunctions are attributed to the disease conditions has been specifically encouraged. Moreover, the epigenetic effects of HNF-1α have been discussed here, which could help in advanced technologies for molecular pharmacological intervention and potential clinical implications for targeted therapies. HNF-1α plays an indispensable role in several physiological mechanisms in the liver, pancreas, intestine, and kidney. Loss of its operations leads to the non-functional or abnormal functional state of each organ. Specific molecular agents or epigenetic modifying drugs that reactivate HNF-1α are the current requirements for the medications of the diseases.

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Proton-irradiated breast cells: molecular points of view

Journal of Radiation Research ◽

10.1093/jrr/rrz032 ◽

2019 ◽

Vol 60 (4) ◽

pp. 451-465 ◽

Cited By ~ 3

Author(s):

Valentina Bravatà ◽

Francesco P Cammarata ◽

Luigi Minafra ◽

Pietro Pisciotta ◽

Concetta Scazzone ◽

...

Keyword(s):

Cell Line ◽

Cell Fate ◽

Cell Lines ◽

Molecular Mechanisms ◽

Proton Irradiation ◽

Expression Profiles ◽

Treatment Plan ◽

Mcf10a Cell ◽

Specific Cell ◽

Dose Dependent

Abstract Breast cancer (BC) is the most common cancer in women, highly heterogeneous at both the clinical and molecular level. Radiation therapy (RT) represents an efficient modality to treat localized tumor in BC care, although the choice of a unique treatment plan for all BC patients, including RT, may not be the best option. Technological advances in RT are evolving with the use of charged particle beams (i.e. protons) which, due to a more localized delivery of the radiation dose, reduce the dose administered to the heart compared with conventional RT. However, few data regarding proton-induced molecular changes are currently available. The aim of this study was to investigate and describe the production of immunological molecules and gene expression profiles induced by proton irradiation. We performed Luminex assay and cDNA microarray analyses to study the biological processes activated following irradiation with proton beams, both in the non-tumorigenic MCF10A cell line and in two tumorigenic BC cell lines, MCF7 and MDA-MB-231. The immunological signatures were dose dependent in MCF10A and MCF7 cell lines, whereas MDA-MB-231 cells show a strong pro-inflammatory profile regardless of the dose delivered. Clonogenic assay revealed different surviving fractions according to the breast cell lines analyzed. We found the involvement of genes related to cell response to proton irradiation and reported specific cell line- and dose-dependent gene signatures, able to drive cell fate after radiation exposure. Our data could represent a useful tool to better understand the molecular mechanisms elicited by proton irradiation and to predict treatment outcome

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The multi-faceted functioning portrait of LRF/ZBTB7A

Human Genomics ◽

10.1186/s40246-019-0252-0 ◽

2019 ◽

Vol 13 (1) ◽

Cited By ~ 5

Author(s):

Caterina Constantinou ◽

Magda Spella ◽

Vasiliki Chondrou ◽

George P. Patrinos ◽

Adamantia Papachatzopoulou ◽

...

Keyword(s):

Cell Fate ◽

Cellular Response ◽

Molecular Mechanisms ◽

Aerobic Glycolysis ◽

Specific Cell ◽

Regulation Of Transcription ◽

Cancer Type ◽

Cellular Effects ◽

Physiological Processes ◽

Signaling Axis

AbstractTranscription factors (TFs) consisting of zinc fingers combined with BTB (for broad-complex, tram-track, and bric-a-brac) domain (ZBTB) are a highly conserved protein family that comprises a multifunctional and heterogeneous group of TFs, mainly modulating cell developmental events and cell fate. LRF/ZBTB7A, in particular, is reported to be implicated in a wide variety of physiological and cancer-related cell events. These physiological processes include regulation of erythrocyte maturation, B/T cell differentiation, adipogenesis, and thymic insulin expression affecting consequently insulin self-tolerance. In cancer, LRF/ZBTB7A has been reported to act either as oncogenic or as oncosuppressive factor by affecting specific cell processes (proliferation, apoptosis, invasion, migration, metastasis, etc) in opposed ways, depending on cancer type and molecular interactions. The molecular mechanisms via which LRF/ZBTB7A is known to exert either physiological or cancer-related cellular effects include chromatin organization and remodeling, regulation of the Notch signaling axis, cellular response to DNA damage stimulus, epigenetic-dependent regulation of transcription, regulation of the expression and activity of NF-κB and p53, and regulation of aerobic glycolysis and oxidative phosphorylation (Warburg effect). It is a pleiotropic TF, and thus, alterations to its expression status become detrimental for cell survival. This review summarizes its implication in different cellular activities and the commonly invoked molecular mechanisms triggered by LRF/ZBTB7A’s orchestrated action.

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Chromatin-Mediated Restriction of Nuclear Factor 1/CTF Binding in a Repressed and Hormone-Activated Promoter In Vivo

Molecular and Cellular Biology ◽

10.1128/mcb.24.7.3036-3047.2004 ◽

2004 ◽

Vol 24 (7) ◽

pp. 3036-3047 ◽

Cited By ~ 20

Author(s):

Sergey Belikov ◽

Carolina Åstrand ◽

Per-Henrik Holmqvist ◽

Örjan Wrange

Keyword(s):

Dna Binding ◽

Chromatin Remodeling ◽

Gene Networks ◽

Fold Increase ◽

Micrococcal Nuclease ◽

Specific Gene ◽

Nuclear Factor ◽

Mmtv Promoter ◽

Nuclear Factor 1

ABSTRACT Mouse mammary tumor virus (MMTV) promoter-driven transcription is induced by glucocorticoid hormone via binding of the glucocorticoid receptor (GR). The MMTV promoter also harbors a binding site for nuclear factor 1 (NF1). NF1 and GR were expressed in Xenopus oocytes; this revealed GR-NF1 cooperativity both in terms of DNA binding and chromatin remodeling but not transcription. A fraction of NF1 sites were occupied in a hormone-dependent fashion, but a significant and NF1 concentration-dependent fraction were constitutively bound. Activation of the MMTV promoter resulted in an ∼50-fold increase in the NF1 accessibility for its DNA site. The hormone-dependent component of NF1 binding was dissociated by addition of a GR antagonist; however, the antagonist RU486, which supports partial GR-DNA binding, also maintained partial NF1 binding. Hence GR-NF1 cooperativity is independent of agonist-driven chromatin remodeling. NF1 induced the formation of a micrococcal-nuclease-resistant protein-DNA complex containing the DNA segment from −185 to −55, the MMTV enhanceosome. Coexpression of NF1 and Oct1 resulted in a significant stimulation of hormone-induced MMTV transcription and also in increased basal transcription. We propose that hormone-independent NF1 binding may be involved in maintaining transcriptional competence and establishment of tissue-specific gene networks.

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MON-719 The Cellular and Molecular Landscape of Hypothalamic Patterning and Differentiation

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1237 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Thomas Kim

Keyword(s):

Cell Fate ◽

Regulatory Networks ◽

Large Scale ◽

Molecular Mechanisms ◽

Brain Atlas ◽

Specific Gene ◽

Cell Fate Specification ◽

Human Hypothalamus ◽

Fate Specification ◽

Time Points

Abstract The hypothalamus is a central regulator of physiological homeostasis. During development, multiple transcription factors coordinate the patterning and specification of hypothalamic nuclei. However, the molecular mechanisms controlling hypothalamic patterning and cell fate specification are poorly understood. To identify genes that control these processes, we have used single-cell RNA sequencing (scRNA-Seq) to profile mouse hypothalamic gene expression across multiple developmental time points. We have further utilised scRNA-Seq to phenotype mutations in genes that play major roles in early hypothalamic patterning. To first understand hypothalamic development, hypothalami were collected at both embryonic (E10-E16, E18) and postnatal (PN4, PN8, PN14, PN45) time points. At early stages, when the bulk of hypothalamic patterning occurs (E11-E13), we observe a clear separation between mitotic progenitors and postmitotic neural precursor cells. We likewise observed clean segregation among cells expressing regional hypothalamic markers identified in previous large-scale analysis of hypothalamic development. This analysis reveals new region-specific markers and identifies candidate genes for selectively regulating patterning and cell fate specification in individual hypothalamic regions. With our rich dataset of developing mouse hypothalamus, we integrated our dataset with the Allen Brain Atlas in situ data, publicly available adult hypothalamic scRNA-Seq dataset to understand hierarchy of hypothalamic cell differentiation, as well as re-defining cell types of the hypothalamus. We next used scRNA-Seq to phenotype multiple mutant lines, including a line that has been extensively characterised as a proof of concept (Ctnnb1 overexpression), and lines that have not been characterised (Nkx2.1, Nkx2.2, Dlx1/2 deletion). We show that this approach can rapidly and comprehensively characterize mutants that have altered hypothalamic patterning, and in doing so, have identified multiple genes that simultaneously repress posterior hypothalamic identity while promoting prethalamic identity. This result supports a modified columnar model of organization for the diencephalon, where prethalamus and hypothalamus are situated in adjacent dorsal and ventral domains of the anterior diencephalon. These data serve as a resource for further studies of hypothalamic development and dysfunction, and able to delineate transcriptional regulatory networks of hypothalamic formation. Lastly, using our mouse hypothalamus as a guideline, we are comparing dataset of developing chicken, zebrafish and human hypothalamus, to identify evolutionarily conserved and divergent region-specific gene regulatory networks. We aim to use this knowledge and information of key molecular pathways of human hypothalamic development and produce human hypothalamus organoids.

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Molecular Logic of Hypothalamus Development

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1037 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A507-A507

Author(s):

Thomas Kim

Keyword(s):

Transcription Factors ◽

Cell Fate ◽

Regulatory Networks ◽

Molecular Mechanisms ◽

Developmental Time ◽

Specific Gene ◽

Molecular Logic ◽

Hypothalamic Nuclei ◽

Physiological Homeostasis ◽

Mutant Lines

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Single-Cell Genomics: Catalyst for Cell Fate Engineering

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2021.748942 ◽

2021 ◽

Vol 9 ◽

Author(s):

Boxun Li ◽

Gary C. Hon

Keyword(s):

Single Cell ◽

Cell Fate ◽

Molecular Mechanisms ◽

Cell Types ◽

Cellular Heterogeneity ◽

State Transitions ◽

Small Scale ◽

Specific Cell ◽

Direct Reprogramming ◽

Cell State

As we near a complete catalog of mammalian cell types, the capability to engineer specific cell types on demand would transform biomedical research and regenerative medicine. However, the current pace of discovering new cell types far outstrips our ability to engineer them. One attractive strategy for cellular engineering is direct reprogramming, where induction of specific transcription factor (TF) cocktails orchestrates cell state transitions. Here, we review the foundational studies of TF-mediated reprogramming in the context of a general framework for cell fate engineering, which consists of: discovering new reprogramming cocktails, assessing engineered cells, and revealing molecular mechanisms. Traditional bulk reprogramming methods established a strong foundation for TF-mediated reprogramming, but were limited by their small scale and difficulty resolving cellular heterogeneity. Recently, single-cell technologies have overcome these challenges to rapidly accelerate progress in cell fate engineering. In the next decade, we anticipate that these tools will enable unprecedented control of cell state.

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Heterogeneous transcriptome response to DNA damage at single cell resolution

10.1101/737130 ◽

2019 ◽

Author(s):

Sung Rye Park ◽

Sim Namkoong ◽

Zac Zezhi Zhang ◽

Leon Friesen ◽

Yu-Chih Chen ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cancer Cells ◽

Cell Fate ◽

Stress Responses ◽

Cell Cycle Checkpoint ◽

Specific Gene ◽

Specific Cell ◽

Transcriptional Responses ◽

Transcriptome Response

Cancer cells often heterogeneously respond to genotoxic chemotherapy, leading to fractional killing and chemoresistance1, 2, which remain as the major obstacles in cancer treatment. It is widely believed that DNA damage induces a uniform response in regulating transcription and that cell fate is passively determined by a threshold mechanism evaluating the level of transcriptional responses3. On the contrary to this assumption, here we show that a surprisingly high level of heterogeneity exists in individual cell transcriptome responses to DNA damage, and that these transcriptome variations dictate the cell fate after DNA damage. Many DNA damage response genes, including tumor suppressor p53 targets, were exclusively expressed in only a subset of cells having specific cell fate, producing unique stress responses tailored for the fate that the cells are committed to. For instance, CDKN1A, the best known p53 target inhibiting cell cycle, was specifically expressed in a subset of cells undergoing cell cycle checkpoint, while other pro-apoptotic p53 targets were expressed only in cells undergoing apoptosis. A small group of cells exhibited neither checkpoint nor apoptotic responses, but produced a unique transcriptional program that conferred strong chemoresistance to the cells. The heterogeneous transcriptome response to DNA damage was also observed at the protein level in flow cytometry. Our results demonstrate that cell fate heterogeneity after DNA damage is mediated by distinct transcriptional programs generating fate-specific gene expression landscapes. This finding provides an important insight into understanding heterogeneous chemotherapy responses of cancer cells.

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UME6, a Novel Filament-specific Regulator ofCandida albicansHyphal Extension and Virulence

Molecular Biology of the Cell ◽

10.1091/mbc.e07-11-1110 ◽

2008 ◽

Vol 19 (4) ◽

pp. 1354-1365 ◽

Cited By ~ 139

Author(s):

Mohua Banerjee ◽

Delma S. Thompson ◽

Anna Lazzell ◽

Patricia L. Carlisle ◽

Christopher Pierce ◽

...

Keyword(s):

Molecular Mechanisms ◽

Pathogenic Fungi ◽

Filamentous Growth ◽

Specific Gene ◽

Regulatory Pathways ◽

Expression Of Genes ◽

High Level ◽

Germ Tubes

The specific ability of the major human fungal pathogen Candida albicans, as well as many other pathogenic fungi, to extend initial short filaments (germ tubes) into elongated hyphal filaments is important for a variety of virulence-related processes. However, the molecular mechanisms that control hyphal extension have remained poorly understood for many years. We report the identification of a novel C. albicans transcriptional regulator, UME6, which is induced in response to multiple host environmental cues and is specifically important for hyphal extension. Although capable of forming germ tubes, the ume6Δ/ume6Δ mutant exhibits a clear defect in hyphal extension both in vitro and during infection in vivo and is attenuated for virulence in a mouse model of systemic candidiasis. We also show that UME6 is an important downstream component of both the RFG1-TUP1 and NRG1-TUP1 filamentous growth regulatory pathways, and we provide evidence to suggest that Nrg1 and Ume6 function together by a negative feedback loop to control the level and duration of filament-specific gene expression in response to inducing conditions. Our results suggest that hyphal extension is controlled by a specific transcriptional regulatory mechanism and is correlated with the maintenance of high-level expression of genes in the C. albicans filamentous growth program.

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Coordinate Transcription of the ADAMTS-1 Gene by Luteinizing Hormone and Progesterone Receptor

Molecular Endocrinology ◽

10.1210/me.2003-0380 ◽

2004 ◽

Vol 18 (10) ◽

pp. 2463-2478 ◽

Cited By ~ 85

Author(s):

Kari M. H. Doyle ◽

Darryl L. Russell ◽

Venkataraman Sriraman ◽

JoAnne S. Richards

Keyword(s):

Progesterone Receptor ◽

Granulosa Cells ◽

Binding Sites ◽

Promoter Activity ◽

Molecular Mechanisms ◽

Luciferase Reporter ◽

Nuclear Factor ◽

Nuclear Factor 1

Abstract ADAMTS-1 (a disintegrin and metalloproteinase with thrombospondin-like motifs) is a multifunctional protease that is expressed in periovulatory follicles. Herein we show that induction of ADAMTS-1 message in vivo and transcription of the ADAMTS-1 promoter in cultured granulosa cells are dependent on separable but coordinate actions of LH and the progesterone receptor (PR). To analyze the molecular mechanisms by which LH and PR regulate this gene, truncations and site-specific mutants of ADAMTS-1 promoter-luciferase reporter constructs (ADAMTS-1-Luc) were generated and transfected into rat granulosa cell cultures. Three regions of the promoter were found to be important for basal activity, two of which were guanine cytosine-rich binding sites for specificity proteins Sp1/Sp3 and the third bound a nuclear factor 1-like factor. Despite the absence of a consensus PR DNA response element in the proximal ADAMTS-1 promoter, cotransfection of a PRA (or PRB) expression vector stimulated ADAMTS-1 promoter activity, a response that was reduced by the PR antagonist ZK98299. Forskolin plus phorbol myristate acetate also increased promoter activity and, when added to cells cotransfected with PRA, ADAMTS-1 promoter activity increased further. Activation of the ADAMTS-1 promoter by PRA involves functional CAAT enhancer binding protein β, nuclear factor 1-like factor, and three Sp1/Sp3 binding sites as demonstrated by transfection of mutated promoter constructs. In summary, LH and PRA/B exert distinct but coordinate effects on transactivation of the ADAMTS-1 gene in granulosa cells in vivo and in vitro with PR acting as an inducible coregulator of the ADAMTS-1 gene.

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Controlling embryonic stem cell proliferation and pluripotency: the role of PI3K- and GSK-3-dependent signalling

Biochemical Society Transactions ◽

10.1042/bst0390674 ◽

2011 ◽

Vol 39 (2) ◽

pp. 674-678 ◽

Cited By ~ 24

Author(s):

Melanie J. Welham ◽

Emmajayne Kingham ◽

Yolanda Sanchez-Ripoll ◽

Benjamin Kumpfmueller ◽

Michael Storm ◽

...

Keyword(s):

Cell Fate ◽

Molecular Mechanisms ◽

Inner Cell Mass ◽

Glycogen Synthase ◽

Cell Mass ◽

Embryonic Stem ◽

Cell Types ◽

Specific Cell ◽

Human Escs ◽

Phosphoinositide 3 Kinase

ESCs (embryonic stem cells) are derived from the inner cell mass of pre-implantation embryos and are pluripotent, meaning they can differentiate into all of the cells that make up the adult organism. This property of pluripotency makes ESCs attractive as a model system for studying early development and for the generation of specific cell types for use in regenerative medicine and drug screening. In order to harness their potential, the molecular mechanisms regulating ESC pluripotency, proliferation and differentiation (i.e. cell fate) need to be understood so that pluripotency can be maintained during expansion, while differentiation to specific lineages can be induced accurately when required. The present review focuses on the potential roles that PI3K (phosphoinositide 3-kinase) and GSK-3 (glycogen synthase kinase 3)-dependent signalling play in the co-ordination and integration of mouse ESC pluripotency and proliferation and contrast this with our understanding of their functions in human ESCs.

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