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Transcription factor p63 bookmarks and regulates dynamic enhancers during epidermal differentiation

Published on Jun 1, 2015in EMBO Reports8.38
· DOI :10.15252/embr.201439941
Evelyn N. Kouwenhoven8
Estimated H-index: 8
(Radboud University Nijmegen),
Martin Oti11
Estimated H-index: 11
(Radboud University Nijmegen)
+ 5 AuthorsHuiqing Zhou24
Estimated H-index: 24
(Radboud University Nijmegen)
Cite
Abstract
The transcription factor p63 plays a pivotal role in keratinocyte proliferation and differentiation in the epidermis. However, how p63 regulates epidermal genes during differentiation is not yet clear. Using epigenome profiling of differentiating human primary epidermal keratinocytes, we characterized a catalog of dynamically regulated genes and p63-bound regulatory elements that are relevant for epithelial development and related diseases. p63-bound regulatory elements occur as single or clustered enhancers, and remarkably, only a subset is active as defined by the co-presence of the active enhancer mark histone modification H3K27ac in epidermal keratinocytes. We show that the dynamics of gene expression correlates with the activity of p63-bound enhancers rather than with p63 binding itself. The activity of p63-bound enhancers is likely determined by other transcription factors that cooperate with p63. Our data show that inactive p63-bound enhancers in epidermal keratinocytes may be active during the development of other epithelial-related structures such as limbs and suggest that p63 bookmarks genomic loci during the commitment of the epithelial lineage and regulates genes through temporal- and spatial-specific active enhancers.
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  • References (78)
  • Citations (44)
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References78
Newest
Published on Feb 1, 2015in Journal of Investigative Dermatology6.29
Jason M. Rizzo10
Estimated H-index: 10
(UB: University at Buffalo),
Rose-Anne Romano18
Estimated H-index: 18
(UB: University at Buffalo)
+ 1 AuthorsSatrajit Sinha32
Estimated H-index: 32
(UB: University at Buffalo)
Published on Jan 1, 2015in Cell Death & Differentiation8.09
Eleonora Candi38
Estimated H-index: 38
,
Ivano Amelio20
Estimated H-index: 20
(University of Leicester)
+ 1 AuthorsGerry Melino82
Estimated H-index: 82
MicroRNAs (miRs) are a class of small noncoding RNAs that suppress the expression of protein-coding genes by repressing protein translation. Although the roles that miRs and the miR processing machinery have in regulating epithelial stem cell biology are not fully understood, their fundamental contributions to these processes have been demonstrated over the last few years. The p53-family member p63 is an essential transcription factor for epidermal morphogenesis and homeostasis. p63 functions as...
Published on Sep 1, 2014in Nature Reviews Molecular Cell Biology43.35
Archana Shenoy11
Estimated H-index: 11
,
Robert Blelloch39
Estimated H-index: 39
microRNAs (miRNAs) promote and stabilize cells fates during the differentiation of stem and progenitor cells into muscle, blood, skin and neural tissues. These miRNAs are part of complex networks that tightly regulate their function at multiple levels: transcription, biogenesis, stability and target site availability, as well as their cooperation with other miRNAs and RNA- binding proteins.
Published on May 15, 2014in Human Molecular Genetics4.54
Walid D. Fakhouri11
Estimated H-index: 11
(MSU: Michigan State University),
Fedik Rahimov19
Estimated H-index: 19
(UI: University of Iowa)
+ 14 AuthorsYoussef A. Kousa10
Estimated H-index: 10
(MSU: Michigan State University)
DNA variation in Interferon Regulatory Factor 6 (IRF6) causes Van der Woude syndrome (VWS), the most common syndromic form of cleft lip and palate (CLP). However, an etiologic variant in IRF6 has been found in only 70% of VWS families. To test whether DNA variants in regulatory elements cause VWS, we sequenced three conserved elements near IRF6 in 70 VWS families that lack an etiologic mutation within IRF6 exons. A rare mutation (350dupA) was found in a conserved IRF6 enhancer element (MCS9.7) i...
Deepavali Chakravarti9
Estimated H-index: 9
,
Xiaohua Su9
Estimated H-index: 9
+ 18 AuthorsWeimin Xiao4
Estimated H-index: 4
(UH: University of Houston)
Abstract The roles of microRNAs (miRNAs) and the miRNA processing machinery in the regulation of stem cell biology are not well understood. Here, we show that the p53 family member and p63 isoform, ΔNp63, is a transcriptional activator of a cofactor critical for miRNA processing (DGCR8). This regulation gives rise to a unique miRNA signature resulting in reprogramming cells to multipotency. Strikingly, ΔNp63−/− epidermal cells display profound defects in terminal differentiation and express a su...
Published on Feb 1, 2014in Nature Genetics25.45
Lorenzo Pasquali11
Estimated H-index: 11
,
Kyle J. Gaulton25
Estimated H-index: 25
+ 22 AuthorsMartijn van de Bunt23
Estimated H-index: 23
Jorge Ferrer and colleagues have mapped regulatory SNP variants associated in GWAS with type 2 diabetes risk and glycemic traits to large clusters of enhancer elements regulating the transcriptional identity of pancreatic β cells via a highly connected transcription factor network.
Published on Jan 1, 2014in Nucleic Acids Research11.15
Sebastian Köhler33
Estimated H-index: 33
(Charité),
Sandra C. Doelken16
Estimated H-index: 16
(Charité)
+ 44 AuthorsJennifer Campbell1
Estimated H-index: 1
(Newcastle University)
The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with severa...
Published on Jan 1, 2014in Nucleic Acids Research11.15
Kim D. Pruitt31
Estimated H-index: 31
(NIH: National Institutes of Health),
Garth Brown10
Estimated H-index: 10
(NIH: National Institutes of Health)
+ 26 AuthorsKelly M. McGarvey4
Estimated H-index: 4
(NIH: National Institutes of Health)
The National Center for Biotechnology Information (NCBI) Reference Sequence (RefSeq) database is a collection of annotated genomic, transcript and protein sequence records derived from data in public sequence archives and from computation, curation and collaboration (http://www.ncbi.nlm.nih.gov/refseq/). We report here on growth of the mammalian and human subsets, changes to NCBI’s eukaryotic annotation pipeline and modifications affecting transcript and protein records. Recent changes to NCBI’s...
Published on Dec 23, 2013
J Simon1
Estimated H-index: 1
,
Van Heeringen1
Estimated H-index: 1
Published on Aug 1, 2013in American Journal of Medical Genetics Part A2.20
Emma Vernersson Lindahl1
Estimated H-index: 1
(CSHL: Cold Spring Harbor Laboratory),
Elvin L. Garcia4
Estimated H-index: 4
(SBU: Stony Brook University),
Alea A. Mills40
Estimated H-index: 40
(CSHL: Cold Spring Harbor Laboratory)
Human Ectrodactyly, Ectodermal dysplasia, Clefting (EEC) syndrome is an autosomal dominant developmental disorder defined by limb deformities, skin defects, and craniofacial clefting. Although associated with heterozygous missense mutations in TP63, the genetic basis underlying the variable expressivity and incomplete penetrance of EEC is unknown. Here, we show that mice heterozygous for an allele encoding the Trp63 p.Arg318His mutation, which corresponds to the human TP63 p.Arg279His mutation f...
Cited By44
Newest
Published on Jan 1, 2019in Scientific Reports4.01
Sabine E.J. Tanis3
Estimated H-index: 3
(Radboud University Nijmegen),
Elif Senem Koksal (Radboud University Nijmegen)+ 1 AuthorsKlaas W. Mulder14
Estimated H-index: 14
(Radboud University Nijmegen)
As our understanding of transcriptional regulation improves so does our appreciation of its complexity. Both coding and (long) non-coding RNAs provide cells with multiple levels of control and thereby flexibility to adapt gene expression to the environment. However, few long non-coding RNAs (lncRNAs) have been studied in human epidermal stem cells. Here, we characterized the expression of 26 lncRNAs in human epidermal keratinocytes, 7 of which we found to be dynamically expressed during differen...
Published on Dec 1, 2019in Nature Communications11.88
José M. Santos-Pereira6
Estimated H-index: 6
(CSIC: Spanish National Research Council),
Lourdes Gallardo-Fuentes (CSIC: Spanish National Research Council)+ 2 AuthorsJuan J. Tena19
Estimated H-index: 19
(CSIC: Spanish National Research Council)
The transcription factor p63 is a master regulator of ectoderm development. Although previous studies show that p63 triggers epidermal differentiation in vitro, the roles of p63 in developing embryos remain poorly understood. Here, we use zebrafish embryos to analyze in vivo how p63 regulates gene expression during development. We generate tp63-knock-out mutants that recapitulate human phenotypes and show down-regulated epidermal gene expression. Following p63-binding dynamics, we find two disti...
Published on Dec 1, 2019in Epigenetics & Chromatin4.18
Jieqiong Qu2
Estimated H-index: 2
(Radboud University Nijmegen),
Guoqiang Yi (Radboud University Nijmegen), Huiqing Zhou24
Estimated H-index: 24
(Radboud University Nijmegen)
The transcription factor p63 regulates epidermal genes and the enhancer landscape in skin keratinocytes. Its molecular function in controlling the chromatin structure is, however, not yet completely understood. Here, we integrated multi-omics profiles, including the transcriptome, transcription factor DNA-binding and chromatin accessibility, in skin keratinocytes isolated from EEC syndrome patients carrying p63 mutations, to examine the role of p63 in shaping the chromatin architecture. We found...
Published on Sep 1, 2019in Cell Death and Disease5.96
Amjad Aljagthmi1
Estimated H-index: 1
(Wright State University),
Natasha T. Hill3
Estimated H-index: 3
(Wright State University)
+ 4 AuthorsMadhavi P. Kadakia20
Estimated H-index: 20
(Wright State University)
ΔNp63α, a member of the p53 family of transcription factors, is overexpressed in a number of cancers and plays a role in proliferation, differentiation, migration, and invasion. ΔNp63α has been shown to regulate several microRNAs that are involved in development and cancer. We identified miRNA miR-320a as a positively regulated target of ΔNp63α. Previous studies have shown that miR-320a is downregulated in colorectal cancer and targets the small GTPase Rac1, leading to a reduction in noncanonica...
Published on Jul 18, 2019in Oncogene6.63
Shun Yao6
Estimated H-index: 6
,
Hsinyi Huang4
Estimated H-index: 4
(CAS: Chinese Academy of Sciences)
+ 7 AuthorsHongbin Ji44
Estimated H-index: 44
Metastasis is the leading cause of lung cancer-related death. Elucidating the metastasis process can provide new avenues to inhibit this malignant behavior of cancer cells. Here we found that human lung cancers with high Keratin 14 (K14) expression were associated with nodal metastasis and poor survival. Using the KrasG12D/Trp53L/L lung cancer mouse model, we confirmed that K14-high cancer cells harbored increased metastatic potential. Mechanistic investigation revealed that Gastrokine 1 (Gkn1) ...
Published on 2019in Cell Reports7.82
Meng-Hsiung Hsieh1
Estimated H-index: 1
(UTD: University of Texas at Dallas),
Joshua H. Choe (Columbia University)+ 7 AuthorsSimbarashe Mazambani (UTD: University of Texas at Dallas)
Summary Squamous cell carcinoma (SCC), a malignancy arising across multiple anatomical sites, is responsible for significant cancer mortality due to insufficient therapeutic options. Here, we identify exceptional glucose reliance among SCCs dictated by hyperactive GLUT1-mediated glucose influx. Mechanistically, squamous lineage transcription factors p63 and SOX2 transactivate the intronic enhancer cluster of SLC2A1. Elevated glucose influx fuels generation of NADPH and GSH, thereby heightening t...
Published on Jul 23, 2019in International Journal of Molecular Sciences4.18
Michael A. Moses , Andrea George + 4 AuthorsWendy C. Weinberg20
Estimated H-index: 20
The p63 gene is a member of the p53/p63/p73 family of transcription factors and plays a critical role in development and homeostasis of squamous epithelium. p63 is transcribed as multiple isoforms; ΔNp63α, the predominant p63 isoform in stratified squamous epithelium, is localized to the basal cells and is overexpressed in squamous cell cancers of multiple organ sites, including skin, head and neck, and lung. Further, p63 is considered a stem cell marker, and within the epidermis, ΔNp63α directs...
Published on Jun 19, 2019in PLOS ONE2.78
J. Scott Beeler4
Estimated H-index: 4
(Vandy: Vanderbilt University),
Clayton Marshall3
Estimated H-index: 3
(Vandy: Vanderbilt University)
+ 8 AuthorsMelinda E. Sanders37
Estimated H-index: 37
(VUMC: Vanderbilt University Medical Center)
p63 is a transcriptional regulator of ectodermal development that is required for basal cell proliferation and stem cell maintenance. p73 is a closely related p53 family member that is expressed in select p63-positive basal cells and can heterodimerize with p63. p73-/- mice lack multiciliated cells and have reduced numbers of basal epithelial cells in select tissues; however, the role of p73 in basal epithelial cells is unknown. Herein, we show that p73-deficient mice exhibit delayed wound heali...
Published on May 1, 2019in Science Advances
Enrique Lin-Shiao2
Estimated H-index: 2
(UPenn: University of Pennsylvania),
Yemin Lan9
Estimated H-index: 9
+ 7 AuthorsKerstin U. Ludwig26
Estimated H-index: 26
(University Hospital Bonn)
The transcription factor p63 is a key mediator of epidermal development. Point mutations in p63 in patients lead to developmental defects, including orofacial clefting. To date, knowledge on how pivotal the role of p63 is in human craniofacial development is limited. Using an inducible transdifferentiation model, combined with epigenomic sequencing and multicohort meta-analysis of genome-wide association studies data, we show that p63 establishes enhancers at craniofacial development genes to mo...
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