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The role of the SWI/SNF ATP dependent chromatin remodelling complex in the regulation of the human hair follicle cell proliferation and control of the human cutaneous wound healing
Get PDFEpigenetic regulation of gene expression occurs at a number of levels including covalent DNA and histone modifications, nucleosome positioning and ATP-dependent chromatin remodelling as well as higher order chromatin folding and 3D genome organisation. ATP-dependent chromatin remodelling complexes modulate nucleosome structure, positioning and chromatin de-compaction and are involved in gene activation and repression. SWI/SNF ATP-dependent chromatin remodelling complexes contain either BRG1 or BRM as the core ATPase together with other common and variable subunits. BRG1 is required for terminal epidermal differentiation in mice and humans and for hair follicle stem cell activation during mouse hair follicle regeneration and cutaneous wound healing. However, the role of SWI/SNF complexes in human hair growth and wound healing remain unknown.
Here it is demonstrated that genes encoding SWI/SNF complex subunits are expressed in human hair follicles. It also highlights that siRNA mediated suppression of SWI/SNF complexes in hair follicle culture has no effect on hair growth, or anagen-catagen transition in the short term, but a significant increase in proliferation of the outer root sheath keratinocytes was seen. The data also documents the expression of several SWI/SNF subunits in human epidermis and that siRNA mediated SMARCA4 gene suppression in primary human keratinocyte monolayers defined the requirements of BRG1 for wound closure through control of cell migration, but not proliferation.
In summary, this data revealed a diverse SWI/SNF complex subunit composition in human epidermis and hair follicle, and an essential role of the core complex ATPase BRG1 in keratinocyte migration during wound closure and re-epithelisation
Mechanisms of epigenetic regulation in epidermal keratinocytes during skin development. Role of p63 transcription factor in the establishment of lineage-specific gene expression programs in keratinocytes via regulation of nuclear envelope-associated genes and Polycomb chromatin remodelling factors.
No full textDuring tissues development multipotent progenitor cells establish tissue-specific
gene expression programmes, leading to differentiation into specialized cell types. It
has been previously shown that the transcription factor p63, a master regulator of skin
development, controls the expression of adhesion molecules and essential
cytoskeleton components. It has also been shown that p63 plays an important role in
establishing distinct three-dimensional conformations in the Epidermal Differentiation
Complex (EDC) locus (Fessing et al., 2011). Here we show that in p63-null mice about
32% of keratinocytes showed altered nuclear morphology. Alterations in the nuclear
shape were accompanied by decreased expression of nuclear lamins (Lamin A/C and
Lamin B1), proteins of the LINC complex (Sun-1, nesprin-2/3) and Plectin. Plectin links
components of the nuclear envelope (nesprin-3) with cytoskeleton and ChIP-qPCR
assay with adult epidermal keratinocytes showed p63 binding to the consensus binding
sequences on Plectin 1c, Sun-1 and Nesprin-3 promoters.
As a possible consequence of the altered expression of nuclear lamins and
nuclear envelope-associated proteins, changes in heterochromatin distribution as well
as decrease of the expression of several polycomb proteins (Ezh2, Ring1B, Cbx4) has
been observed in p63-null keratinocytes. Moreover, recent data in our lab have showed
that p63 directly regulates Cbx4, a component of the polycomb PRC1 complex.
Here we show that mice lacking Cbx4 displayed a skin phenotype, which partially
resembles the one observed in p63-null mice with reduced epidermal thickness and
keratinocyte proliferation.
All together these data demonstrate that p63-regulated gene expression program
in epidermal keratinocytes includes not only genes encoding adhesion molecules,
cytoskeleton proteins (cytokeratins) and chromatin remodelling factors (Satb1, Brg1),
but also polycomb proteins and components of the nuclear envelope, suggesting the
existence of a functional link between cytoskeleton, nuclear architecture and three
dimensional nuclear organization.
Other proteins important for proper epidermal development and stratification, are
cytokeratins. Here, we show that keratin genes play an essential role in spatial
organization of other lineage-specific genes in keratinocytes during epidermal
development. In fact, ablation of keratin type II locus from chromosome 15 in epidermal
keratinocytes led to changes in the genomic organization with increased distance
between the Loricrin gene located on chromosome 3 as well as between Satb1 gene
located on chromosome 17 and keratin type II locus, resulting in a more peripheral
localization of these genes in the nucleus. As a possible consequence of their
peripheral localization, reduced expression of Loricrin and Satb1 has also been
observed in keratins type II-deficient mice. These findings together with recent
circularized chromosome conformation capture (4C) data, strongly suggest that keratin
5, Loricrin and Satb1 are part of the same interactome, which is required for the proper
expression of these genes and proper epidermal development and epidermal barrier
formation.
Taken together these data suggest that higher order chromatin remodelling and
spatial organization of genes in the nucleus are important for the establishment of
lineage-specific differentiation programs in epidermal progenitor cells. These data
provide an important background for further analyses of nuclear architecture in the
alterations of epidermal differentiation, seen in pathological conditions, such as
psoriasis and epithelial skin cancers
Chromatin architecture and transcriptional regulation at the Epidermal Differentiation Complex (EDC) locus. The role of epigenetic factors in modulating chromatin structure and tissue-specific gene expression at the murine EDC locus during epidermal differentiation.
No full textThe epidermal differentiation complex (EDC) encodes co-ordinately regulated genes critically involved in epidermal differentiation, however knowledge of the molecular mechanisms involved in co-ordinating EDC gene expression is limited.
Recent findings indicate p63 dependent changes in the nuclear localisation and higher-order chromatin folding the EDC coincide with the onset of epidermal stratification during embryonic development. Here it is demonstrated that a direct transcription target of p63, the chromatin-remodelling enzyme Brg1, modulates the specific nuclear positioning of the EDC and transcription of differentiation-specific gene encoded at the EDC.
In addition, the results of high-resolution 5C-based analyses of the spatial chromatin interactome at a 5.3Mb region spanning the murine EDC in epidermal keratinocytes, and the silenced EDC in thymocytes, are presented. Chromatin interactions at the EDC region in keratinocytes include long-range interactions between multiple proximal and distal candidate gene regulatory regions. Many candidate regulatory elements involved in looping chromatin interactions at the EDC region are enriched for both active (H3K4me1, H3K27ac) and repressive (H3K27me3) chromatin marks and are bound by Sin3a and RBP2 co-repressor complexes.
The chromatin interactome at the EDC in epidermal progenitor cells is enriched for bound chromatin architectural proteins Satb1, Satb2, and the cohesin subunit Rad21. Further, a substantial degree of co-localisation is observed between these chromatin architectural proteins, transcription factors and co-factors.
Findings presented here suggest that a functional chromatin interactome, mediated by Satb proteins and cohesin, acts in conjunction with transcriptional repressor complexes to facilitate co-ordinated gene expression at the EDC in epidermal progenitor cells upon differentiation. These results provide a foundation for further study of the mechanisms controlling EDC gene expression in health and disease
Gene Regulation at a Distance: Higher-Order Chromatin Folding and the Coordinated Control of Gene Transcription at the Epidermal Differentiation Complex Locus
No full textNoChromatin structure and spatial interactions between proximal and distal gene regulatory elements, including gene core promoters and enhancers, are important in the control of gene transcription. In this issue, Oh et al. characterized an AP-1-dependent enhancer at the epidermal differentiation complex locus that establishes spatial interactions with numerous gene promoter regions at that locus
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Epigenetic Regulation of Skin Development and Postnatal Homeostasis The role of chromatin architectural protein Ctcf in the control of Keratinocyte Differentiation and Epidermal Barrier Formation
Get PDFEpigenetic regulatory mechanisms play important roles in the control of lineage-specific differentiation during development. However, mechanisms that regulate higher-order chromatin remodelling and transcription of keratinocyte-specific genes that are clustered in the genome into three distinct loci (Keratin type I/II loci and Epidermal Differentiation Complex (EDC) during differentiation of the epidermis are poorly understood. By using 3D-Fluorescent In Situ Hybridization (FISH), we determined that in the epidermal keratinocytes, the KtyII and EDC loci are located closely to each other in the nuclear compartment enriched by the nuclear speckles. However, in KtyII locus knockout mice, EDC locus moved away from the KtyII locus flanking regions and nuclear speckles towards the nuclear periphery, which is associated with marked changes in gene expression described previously. Chromatin architectural protein Ctcf has previously been implicated in the control of long-range enhancer-promoter contacts and inter-chromosomal interactions. Ctcf is broadly expressed in the skin including epidermal keratinocytes and hair follicles. Conditional Keratin 14-driven Ctcf ablation in mice results in the increase of the epidermal thickness, proliferation, alterations of the epidermal barrier and the development of epidermal pro-inflammatory response. Epidermal barrier defects in Krt14CreER/Ctcf fl/fl mice are associated with marked changes in gene expression in the EDC and KtyII loci, which become topologically segregated in the nucleus upon Ctcf ablation. Therefore, these data suggest that Ctcf serves as critical determinant regulating higher-order chromatin organization in lineage-specific gene loci in epidermal keratinocytes, which is required for the proper control of gene expression, maintenance of the epidermal barrier and its function
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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