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      Control of Cell Identity by the Nuclear Receptor HNF4 in Organ Pathophysiology

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          Abstract

          Hepatocyte Nuclear Factor 4 (HNF4) is a transcription factor (TF) belonging to the nuclear receptor family whose expression and activities are restricted to a limited number of organs including the liver and gastrointestinal tract. In this review, we present robust evidence pointing to HNF4 as a master regulator of cellular differentiation during development and a safekeeper of acquired cell identity in adult organs. Importantly, we discuss that transient loss of HNF4 may represent a protective mechanism upon acute organ injury, while prolonged impairment of HNF4 activities could contribute to organ dysfunction. In this context, we describe in detail mechanisms involved in the pathophysiological control of cell identity by HNF4, including how HNF4 works as part of cell-specific TF networks and how its expression/activities are disrupted in injured organs.

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          Epithelial-mesenchymal transitions in development and disease.

          Jean Paul Thiery, Hervé Acloque, Ruby Y J Huang … (2009)
          The epithelial to mesenchymal transition (EMT) plays crucial roles in the formation of the body plan and in the differentiation of multiple tissues and organs. EMT also contributes to tissue repair, but it can adversely cause organ fibrosis and promote carcinoma progression through a variety of mechanisms. EMT endows cells with migratory and invasive properties, induces stem cell properties, prevents apoptosis and senescence, and contributes to immunosuppression. Thus, the mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.
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            Master transcription factors and mediator establish super-enhancers at key cell identity genes.

            Warren A Whyte, David Orlando, Denes Hnisz … (2013)
            Master transcription factors Oct4, Sox2, and Nanog bind enhancer elements and recruit Mediator to activate much of the gene expression program of pluripotent embryonic stem cells (ESCs). We report here that the ESC master transcription factors form unusual enhancer domains at most genes that control the pluripotent state. These domains, which we call super-enhancers, consist of clusters of enhancers that are densely occupied by the master regulators and Mediator. Super-enhancers differ from typical enhancers in size, transcription factor density and content, ability to activate transcription, and sensitivity to perturbation. Reduced levels of Oct4 or Mediator cause preferential loss of expression of super-enhancer-associated genes relative to other genes, suggesting how changes in gene expression programs might be accomplished during development. In other more differentiated cells, super-enhancers containing cell-type-specific master transcription factors are also found at genes that define cell identity. Super-enhancers thus play key roles in the control of mammalian cell identity. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Chromatin accessibility and the regulatory epigenome

              Sandy L. Klemm, Zohar Shipony, William J Greenleaf (2019)
              Physical access to DNA is a highly dynamic property of chromatin that plays an essential role in establishing and maintaining cellular identity. The organization of accessible chromatin across the genome reflects a network of permissible physical interactions through which enhancers, promoters, insulators and chromatin-binding factors cooperatively regulate gene expression. This landscape of accessibility changes dynamically in response to both external stimuli and developmental cues, and emerging evidence suggests that homeostatic maintenance of accessibility is itself dynamically regulated through a competitive interplay between chromatin-binding factors and nucleosomes. In this Review, we examine how the accessible genome is measured and explore the role of transcription factors in initiating accessibility remodelling; our goal is to illustrate how chromatin accessibility defines regulatory elements within the genome and how these epigenetic features are dynamically established to control gene expression.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cells
                Journal ID (iso-abbrev): Cells
                Journal ID (publisher-id): cells
                Title: Cells
                Publisher: MDPI
                ISSN (Electronic): 2073-4409
                Publication date (Electronic): 28 September 2020
                Publication date Collection: October 2020
                Volume: 9
                Issue: 10
                Electronic Location Identifier: 2185
                Affiliations
                [1 ]Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, B-3000 Leuven, Belgium
                [2 ]U1011-EGID, Institut Pasteur de Lille, CHU Lille, Inserm, Univ. Lille, F-59000 Lille, France; bart.staels@ 123456pasteur-lille.fr (B.S.); philippe-claude.lefebvre@ 123456inserm.fr (P.L.)
                [3 ]Department of Genetics, Rutgers University, Piscataway, NJ 08854, USA; verzi@ 123456dls.rutgers.edu
                Author notes
                [* ]Correspondence: vanessa.dubois@ 123456kuleuven.be (V.D.); jerome.eeckhoute@ 123456inserm.fr (J.E.); Tel.: +32-16-3232 (V.D.); +33-3-20974219 (J.E.)
                Author information
                https://orcid.org/0000-0001-8894-2980
                https://orcid.org/0000-0002-3784-1503
                https://orcid.org/0000-0002-7222-9264
                Article
                Publisher ID: cells-09-02185
                DOI: 10.3390/cells9102185
                PMC ID: 7600215
                PubMed ID: 32998360
                SO-VID: 1c1efd08-e4df-4fef-ae24-1f3cfd7d7c61
                Copyright © © 2020 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 08 September 2020
                Date accepted : 26 September 2020
                Categories
                Subject: Review

                Keywords: hnf4 nuclear receptor,cell identity,functional genomics,liver and gastrointestinal pathophysiology
                Data availability:
                Keywords: hnf4 nuclear receptor, cell identity, functional genomics, liver and gastrointestinal pathophysiology

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