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1.
Dev Dyn ; 251(9): 1490-1508, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-34240503

RESUMO

BACKGROUND: Animals develop skin regional specificities to best adapt to their environments. Birds are excellent models in which to study the epigenetic mechanisms that facilitate these adaptions. Patients suffering from SATB2 mutations exhibit multiple defects including ectodermal dysplasia-like changes. The preferential expression of SATB2, a chromatin regulator, in feather-forming compared to scale-forming regions, suggests it functions in regional specification of chicken skin appendages by acting on either differentiation or morphogenesis. RESULTS: Retrovirus mediated SATB2 misexpression in developing feathers, beaks, and claws causes epidermal differentiation abnormalities (e.g. knobs, plaques) with few organ morphology alterations. Chicken ß-keratins are encoded in 5 sub-clusters (Claw, Feather, Feather-like, Scale, and Keratinocyte) on Chromosome 25 and a large Feather keratin cluster on Chromosome 27. Type I and II α-keratin clusters are located on Chromosomes 27 and 33, respectively. Transcriptome analyses showed these keratins (1) are often tuned up or down collectively as a sub-cluster, and (2) these changes occur in a temporo-spatial specific manner. CONCLUSIONS: These results suggest an organizing role of SATB2 in cluster-level gene co-regulation during skin regional specification.


Assuntos
beta-Queratinas , Animais , Galinhas/genética , Plumas/metabolismo , Queratinas/genética , Queratinas/metabolismo , Família Multigênica , beta-Queratinas/genética , beta-Queratinas/metabolismo
2.
Genes (Basel) ; 12(8)2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34440465

RESUMO

The epidermal differentiation complex (EDC) encodes a group of unique proteins expressed in late epidermal differentiation. The EDC gave integuments new physicochemical properties and is critical in evolution. Recently, we showed ß-keratins, members of the EDC, undergo gene cluster switching with overexpression of SATB2 (Special AT-rich binding protein-2), considered a chromatin regulator. We wondered whether this unique regulatory mechanism is specific to ß-keratins or may be derived from and common to EDC members. Here we explore (1) the systematic expression patterns of non-ß-keratin EDC genes and their preferential expression in different skin appendages during development, (2) whether the expression of non-ß-keratin EDC sub-clusters are also regulated in clusters by SATB2. We analyzed bulk RNA-seq and ChIP-seq data and also evaluated the disrupted expression patterns caused by overexpressing SATB2. The results show that the expression of whole EDDA and EDQM sub-clusters are possibly mediated by enhancers in E14-feathers. Overexpressing SATB2 down-regulates the enriched EDCRP sub-cluster in feathers and the EDCH sub-cluster in beaks. These results reveal the potential of complex epigenetic regulation activities within the avian EDC, implying transcriptional regulation of EDC members acting at the gene and/or gene cluster level in a temporal and skin regional-specific fashion, which may contribute to the evolution of diverse avian integuments.


Assuntos
Epiderme/crescimento & desenvolvimento , Tegumento Comum/crescimento & desenvolvimento , Proteínas de Ligação à Região de Interação com a Matriz/genética , beta-Queratinas/genética , Animais , Proteínas Aviárias/genética , Aves/genética , Aves/crescimento & desenvolvimento , Diferenciação Celular/genética , Cromossomos/genética , Epiderme/metabolismo , Epigênese Genética/genética , Evolução Molecular , Plumas/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Pele/crescimento & desenvolvimento , Pele/metabolismo , Fatores de Transcrição/genética
3.
Nat Commun ; 12(1): 2595, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972536

RESUMO

Tissue regeneration is a process that recapitulates and restores organ structure and function. Although previous studies have demonstrated wound-induced hair neogenesis (WIHN) in laboratory mice (Mus), the regeneration is limited to the center of the wound unlike those observed in African spiny (Acomys) mice. Tissue mechanics have been implicated as an integral part of tissue morphogenesis. Here, we use the WIHN model to investigate the mechanical and molecular responses of laboratory and African spiny mice, and report these models demonstrate opposing trends in spatiotemporal morphogenetic field formation with association to wound stiffness landscapes. Transcriptome analysis and K14-Cre-Twist1 transgenic mice show the Twist1 pathway acts as a mediator for both epidermal-dermal interactions and a competence factor for periodic patterning, differing from those used in development. We propose a Turing model based on tissue stiffness that supports a two-scale tissue mechanics process: (1) establishing a morphogenetic field within the wound bed (mm scale) and (2) symmetry breaking of the epidermis and forming periodically arranged hair primordia within the morphogenetic field (µm scale). Thus, we delineate distinct chemo-mechanical events in building a Turing morphogenesis-competent field during WIHN of laboratory and African spiny mice and identify its evo-devo advantages with perspectives for regenerative medicine.


Assuntos
Epiderme/anatomia & histologia , Epiderme/metabolismo , Folículo Piloso/metabolismo , Morfogênese/fisiologia , Regeneração/fisiologia , Proteína 1 Relacionada a Twist/metabolismo , Cicatrização/fisiologia , Animais , Epiderme/fisiologia , Perfilação da Expressão Gênica , Folículo Piloso/anatomia & histologia , Folículo Piloso/fisiologia , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise em Microsséries , Microscopia de Força Atômica , Modelos Psicológicos , Morfogênese/genética , Murinae , RNA-Seq , Regeneração/genética , Medicina Regenerativa , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Análise Espaço-Temporal , Proteína 1 Relacionada a Twist/genética , Cicatrização/genética
4.
Curr Opin Genet Dev ; 69: 103-111, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33780743

RESUMO

Birds are the most diversified terrestrial vertebrates due to highly diverse integumentary organs that enable robust adaptability to various eco-spaces. Here we show that this complexity is built upon multi-level regional specifications. Across-the-body (macro-) specification includes the evolution of beaks and feathers as new integumentary organs that are formed with regional specificity. Within-an-organ (micro-) specification involves further modifications of organ shapes. We review recent progress in elucidating the molecular mechanisms underlying feather diversification as an example. (1) ß-Keratin gene clusters are regulated by typical enhancers or high order chromatin looping to achieve macro- and micro-level regional specification, respectively. (2) Multi-level symmetry-breaking of feather branches confers new functional forms. (3) Complex color patterns are produced by combinations of macro-patterning and micro-patterning processes. The integration of these findings provides new insights toward the principle of making a robustly adaptive bio-interface.


Assuntos
Adaptação Fisiológica/genética , Evolução Biológica , Aves/fisiologia , Tegumento Comum/fisiologia , Animais , Bico/anatomia & histologia , Bico/fisiologia , Aves/genética , Plumas/anatomia & histologia , Plumas/fisiologia , Tegumento Comum/anatomia & histologia , Pele/anatomia & histologia , Vertebrados/genética , Vertebrados/fisiologia
5.
Dev Cell ; 53(5): 561-576.e9, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32516596

RESUMO

Regional specification is critical for skin development, regeneration, and evolution. The contribution of epigenetics in this process remains unknown. Here, using avian epidermis, we find two major strategies regulate ß-keratin gene clusters. (1) Over the body, macro-regional specificities (scales, feathers, claws, etc.) established by typical enhancers control five subclusters located within the epidermal differentiation complex on chromosome 25; (2) within a feather, micro-regional specificities are orchestrated by temporospatial chromatin looping of the feather ß-keratin gene cluster on chromosome 27. Analyses suggest a three-factor model for regional specification: competence factors (e.g., AP1) make chromatin accessible, regional specifiers (e.g., Zic1) target specific genome regions, and chromatin regulators (e.g., CTCF and SATBs) establish looping configurations. Gene perturbations disrupt morphogenesis and histo-differentiation. This chicken skin paradigm advances our understanding of how regulation of big gene clusters can set up a two-dimensional body surface map.


Assuntos
Proteínas Aviárias/metabolismo , Fator de Ligação a CCCTC/metabolismo , Montagem e Desmontagem da Cromatina , Células Epiteliais/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Morfogênese , beta-Queratinas/genética , Animais , Proteínas Aviárias/genética , Fator de Ligação a CCCTC/genética , Diferenciação Celular , Embrião de Galinha , Cromossomos/genética , Células Epiteliais/citologia , Plumas/citologia , Plumas/embriologia , Plumas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Família Multigênica
6.
Proc Natl Acad Sci U S A ; 116(14): 6884-6890, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30886106

RESUMO

Animal skin pigment patterns are excellent models to study the mechanism of biological self-organization. Theoretical approaches developed mathematical models of pigment patterning and molecular genetics have brought progress; however, the responsible cellular mechanism is not fully understood. One long unsolved controversy is whether the patterning information is autonomously determined by melanocytes or nonautonomously determined from the environment. Here, we transplanted purified melanocytes and demonstrated that melanocytes could form periodic pigment patterns cell autonomously. Results of heterospecific transplantation among quail strains are consistent with this finding. Further, we observe that developing melanocytes directly connect with each other via filopodia to form a network in culture and in vivo. This melanocyte network is reminiscent of zebrafish pigment cell networks, where connexin is implicated in stripe formation via genetic studies. Indeed, we found connexin40 (cx40) present on developing melanocytes in birds. Stripe patterns can form in quail skin explant cultures. Several calcium channel modulators can enhance or suppress pigmentation globally, but a gap junction inhibitor can change stripe patterning. Most interestingly, in ovo, misexpression of dominant negative cx40 expands the black region, while overexpression of cx40 expands the yellow region. Subsequently, melanocytes instruct adjacent dermal cells to express agouti signaling protein (ASIP), the regulatory factor for pigment switching, which promotes pheomelanin production. Thus, we demonstrate Japanese quail melanocytes have an autonomous periodic patterning role during body pigment stripe formation. We also show dermal agouti stripes and how the coupling of melanocytes with dermal cells may confer stable and distinct pigment stripe patterns.


Assuntos
Galinhas/metabolismo , Codorniz/metabolismo , Pigmentação da Pele/fisiologia , Pele/metabolismo , Animais , Proteínas Aviárias/metabolismo , Embrião de Galinha , Conexinas/metabolismo , Melanócitos/citologia , Pele/citologia , Proteína alfa-5 de Junções Comunicantes
7.
Exp Dermatol ; 28(4): 480-484, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30916811

RESUMO

Keloids are wounding-induced fibroproliferative human tumor-like skin scars of complex genetic makeup and poorly defined pathogenesis. To reveal dynamic epigenetic and transcriptome changes of keloid fibroblasts, we performed RNA-seq and ATAC-seq analysis on an early passage keloid fibroblast cell strain and its paired normal control fibroblasts. This keloid strain produced keloid-like scars in a plasma clot-based skin equivalent humanized keloid animal model. RNA-seq analysis reveals gene ontology terms including hepatic fibrosis, Wnt-ß-catenin, TGF-ß, regulation of epithelial-mesenchymal transition (EMT), STAT3 and adherens junction. ATAC-seq analysis suggests STAT3 signalling is the most significantly enriched gene ontology term in keloid fibroblasts, followed by Wnt signalling (Wnt5) and regulation of the EMT pathway. Immunohistochemistry confirms that STAT3 (Tyr705 phospho-STAT3) is activated and ß-catenin is up-regulated in the dermis of keloid clinical specimens and keloid skin equivalent implants from the humanized mouse model. A non-linear dose-response of cucurbitacin I, a selective JAK2/STAT3 inhibitor, in collagen type I expression of keloid-derived plasma clot-based skin equivalents implicates a likely role of STAT3 signalling in keloid pathogenesis. This work also demonstrates the utility of the recently established humanized keloid mouse model in exploring the mechanism of keloid formation.


Assuntos
Queloide/etiologia , Queloide/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Humanos , Camundongos , Transcriptoma , Via de Sinalização Wnt
8.
BMC Genomics ; 19(1): 780, 2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30373532

RESUMO

BACKGROUND: The molecular mechanism controlling regional specific skin appendage phenotypes is a fundamental question that remains unresolved. We recently identified feather and scale primordium associated genes and with functional studies, proposed five major modules are involved in scale-to-feather conversion and their integration is essential to form today's feathers. Yet, how the molecular networks are wired and integrated at the genomic level is still unknown. RESULTS: Here, we combine classical recombination experiments and systems biology technology to explore the molecular mechanism controlling cell fate specification. In the chimeric explant, dermal fate is more stable, while epidermal fate is reprogrammed to be similar to the original appendage type of the mesenchyme. We analyze transcriptome changes in both scale-to-feather and feather-to-scale transition in the epidermis. We found a highly interconnected regulatory gene network controlling skin appendage types. These gene networks are organized around two molecular hubs, ß-catenin and retinoic acid (RA), which can bind to regulatory elements controlling downstream gene expression, leading to scale or feather fates. ATAC sequencing analyses revealed about 1000 altered widely distributed chromatin open sites. We find that perturbation of a key gene alters the expression of many other co-expressed genes in the same module. CONCLUSIONS: Our findings suggest that these feather / scale fate specification genes form an interconnected network and rewiring of the gene network can lead to changes of appendage phenotypes, acting similarly to endogenous reprogramming at the tissue level. This work shows that key hub molecules, ß-catenin and retinoic acid, regulate scale / feather fate specification gene networks, opening up new possibilities to understand the switches controlling organ phenotypes in a two component (epithelial and mesenchyme) system.


Assuntos
Plumas , Perfilação da Expressão Gênica , Estudos de Associação Genética , Fenótipo , Pele , Transcriptoma , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes , Especificidade de Órgãos/genética , Elementos de Resposta , Tretinoína/farmacologia
9.
Sci Rep ; 6: 26509, 2016 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-27211601

RESUMO

Promyelocytic leukemia nuclear bodies (PML-NBs) are PML-based nuclear structures that regulate various cellular processes. SUMOylation, the process of covalently conjugating small ubiquitin-like modifiers (SUMOs), is required for both the formation and the disruption of PML-NBs. However, detailed mechanisms of how SUMOylation regulates these processes remain unknown. Here we report that SUMO5, a novel SUMO variant, mediates the growth and disruption of PML-NBs. PolySUMO5 conjugation of PML at lysine 160 facilitates recruitment of PML-NB components, which enlarges PML-NBs. SUMO5 also increases polySUMO2/3 conjugation of PML, resulting in RNF4-mediated disruption of PML-NBs. The acute promyelocytic leukemia oncoprotein PML-RARα blocks SUMO5 conjugation of PML, causing cytoplasmic displacement of PML and disruption of PML-NBs. Our work not only identifies a new member of the SUMO family but also reveals the mechanistic basis of the PML-NB life cycle in human cells.


Assuntos
Núcleo Celular/metabolismo , Lisina/metabolismo , Proteína da Leucemia Promielocítica/genética , Proteína da Leucemia Promielocítica/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Animais , Linhagem Celular Tumoral , Núcleo Celular/genética , Clonagem Molecular , Regulação da Expressão Gênica , Células HEK293 , Células HeLa , Humanos , Células K562 , Células MCF-7 , Camundongos , Células NIH 3T3 , Proteínas Nucleares/metabolismo , Especificidade de Órgãos , Proteína da Leucemia Promielocítica/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética , Sumoilação , Fatores de Transcrição/metabolismo , Ubiquitinas/metabolismo
10.
Biochem Biophys Res Commun ; 431(1): 58-64, 2013 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-23291187

RESUMO

Poly(ADP-ribose) polymerase-2 (PARP-2) catalyzes poly(ADP-ribosyl)ation (PARylation) and regulates numerous nuclear processes, including transcription. Depletion of PARP-2 alters the activity of transcription factors and global gene expression. However, the molecular action of how PARP-2 controls the transcription of target promoters remains unclear. Here we report that PARP-2 possesses transcriptional repression activity independently of its enzymatic activity. PARP-2 interacts and recruits histone deacetylases HDAC5 and HDAC7, and histone methyltransferase G9a to the promoters of cell cycle-related genes, generating repressive chromatin signatures. Our findings propose a novel mechanism of PARP-2 in transcriptional regulation involving specific protein-protein interactions and highlight the importance of PARP-2 in the regulation of cell cycle progression.


Assuntos
Ciclo Celular/genética , Regulação da Expressão Gênica , Histonas/metabolismo , Poli Adenosina Difosfato Ribose/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Fase G1/genética , Células HEK293 , Antígenos de Histocompatibilidade/metabolismo , Histona Desacetilases/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Metilação , Poli(ADP-Ribose) Polimerases/genética , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myc/genética , Fator de Transcrição YY1/metabolismo
11.
Curr Opin Pharmacol ; 11(4): 301-7, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21489876

RESUMO

FK506-binding proteins (FKBPs) are intracellular receptors for FK506 and rapamycin, immunosuppressants that have recently been utilized as anticancer drugs. In the cytoplasm, FKBPs and these drugs modulate signal transduction pathways. However, recent reports reveal novel functions of FKBPs in the nucleus, which include regulation of transcription factors, histone chaperone activity, and modifications of chromatin structure. These activities are known to affect gene expression, DNA repair, and DNA replication. Therefore, elucidation of the nuclear functions of FKBPs will help researchers and clinicians better understand how immunosuppressants work as anticancer drugs, which might in turn lead to novel designs of cancer therapy.


Assuntos
Cromatina/metabolismo , Neoplasias/patologia , Proteínas de Ligação a Tacrolimo/metabolismo , Animais , Antineoplásicos/farmacologia , Desenho de Fármacos , Humanos , Imunossupressores/farmacologia , Transdução de Sinais , Sirolimo/farmacologia , Tacrolimo/farmacologia
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