Abstract:
:Mutations in the gene encoding transcription factor TFAP2A result in pigmentation anomalies in model organisms and premature hair graying in humans. However, the pleiotropic functions of TFAP2A and its redundantly-acting paralogs have made the precise contribution of TFAP2-type activity to melanocyte differentiation unclear. Defining this contribution may help to explain why TFAP2A expression is reduced in advanced-stage melanoma compared to benign nevi. To identify genes with TFAP2A-dependent expression in melanocytes, we profile zebrafish tissue and mouse melanocytes deficient in Tfap2a, and find that expression of a small subset of genes underlying pigmentation phenotypes is TFAP2A-dependent, including Dct, Mc1r, Mlph, and Pmel. We then conduct TFAP2A ChIP-seq in mouse and human melanocytes and find that a much larger subset of pigmentation genes is associated with active regulatory elements bound by TFAP2A. These elements are also frequently bound by MITF, which is considered the "master regulator" of melanocyte development. For example, the promoter of TRPM1 is bound by both TFAP2A and MITF, and we show that the activity of a minimal TRPM1 promoter is lost upon deletion of the TFAP2A binding sites. However, the expression of Trpm1 is not TFAP2A-dependent, implying that additional TFAP2 paralogs function redundantly to drive melanocyte differentiation, which is consistent with previous results from zebrafish. Paralogs Tfap2a and Tfap2b are both expressed in mouse melanocytes, and we show that mouse embryos with Wnt1-Cre-mediated deletion of Tfap2a and Tfap2b in the neural crest almost completely lack melanocytes but retain neural crest-derived sensory ganglia. These results suggest that TFAP2 paralogs, like MITF, are also necessary for induction of the melanocyte lineage. Finally, we observe a genetic interaction between tfap2a and mitfa in zebrafish, but find that artificially elevating expression of tfap2a does not increase levels of melanin in mitfa hypomorphic or loss-of-function mutants. Collectively, these results show that TFAP2 paralogs, operating alongside lineage-specific transcription factors such as MITF, directly regulate effectors of terminal differentiation in melanocytes. In addition, they suggest that TFAP2A activity, like MITF activity, has the potential to modulate the phenotype of melanoma cells.
journal_name
PLoS Genetjournal_title
PLoS geneticsauthors
Seberg HE,Van Otterloo E,Loftus SK,Liu H,Bonde G,Sompallae R,Gildea DE,Santana JF,Manak JR,Pavan WJ,Williams T,Cornell RAdoi
10.1371/journal.pgen.1006636subject
Has Abstractpub_date
2017-03-01 00:00:00pages
e1006636issue
3eissn
1553-7390issn
1553-7404pii
PGENETICS-D-16-02256journal_volume
13pub_type
杂志文章相关文献
PLoS Genetics文献大全abstract::Genome-wide association studies (GWAS) have identified >500 common variants associated with quantitative metabolic traits, but in aggregate such variants explain at most 20-30% of the heritable component of population variation in these traits. To further investigate the impact of genotypic variation on metabolic trai...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004147
更新日期:2014-01-30 00:00:00
abstract::RNA interference (RNAi) related pathways are essential for germline development and fertility in metazoa and can contribute to inter- and trans-generational inheritance. In the nematode Caenorhabditis elegans, environmental double-stranded RNA provided by feeding can lead to heritable changes in phenotype and gene exp...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1007905
更新日期:2019-02-08 00:00:00
abstract::UV-induced DNA damage causes repression of RNA synthesis. Following the removal of DNA lesions, transcription recovery operates through a process that is not understood yet. Here we show that knocking-out of the histone methyltransferase DOT1L in mouse embryonic fibroblasts (MEF(DOT1L)) leads to a UV hypersensitivity ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003611
更新日期:2013-01-01 00:00:00
abstract::The mechanisms involved in the recognition of microbial pathogens and activation of the immune system have been extensively studied. However, the mechanisms involved in the recovery phase of an infection are incompletely characterized at both the cellular and physiological levels. Here, we establish a Caenorhabditis e...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004609
更新日期:2014-10-23 00:00:00
abstract::Genome reduction has been observed in many bacterial lineages that have adapted to specialized environments. The extreme genome degradation seen for obligate pathogens and symbionts appears to be dominated by genetic drift. In contrast, for free-living organisms with reduced genomes, the dominant force is proposed to ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1002651
更新日期:2012-01-01 00:00:00
abstract::Chromatin assembly mutants accumulate recombinogenic DNA damage and are sensitive to genotoxic agents. Here we have analyzed why impairment of the H3K56 acetylation-dependent CAF1 and Rtt106 chromatin assembly pathways, which have redundant roles in H3/H4 deposition during DNA replication, leads to genetic instability...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1002376
更新日期:2011-11-01 00:00:00
abstract::70 kDa heat shock proteins (Hsp70) are essential chaperones of the protein quality control network; vital for cellular fitness and longevity. The four cytosolic Hsp70's in yeast, Ssa1-4, are thought to be functionally redundant but the absence of Ssa1 and Ssa2 causes a severe reduction in cellular reproduction and acc...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1008951
更新日期:2021-01-11 00:00:00
abstract::Mitotic divisions depend on the timely assembly and proper orientation of the mitotic spindle. Malfunctioning of these processes can considerably delay mitosis, thereby compromising tissue growth and homeostasis, and leading to chromosomal instability. Loss of functional Mms19 drastically affects the growth and develo...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1008913
更新日期:2020-11-19 00:00:00
abstract::Although tumor size and lymph node involvement are the current cornerstones of breast cancer prognosis, they have not been extensively explored in relation to tumor methylation attributes in conjunction with other tumor and patient dietary and hormonal characteristics. Using primary breast tumors from 162 (AJCC stage ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1001043
更新日期:2010-07-29 00:00:00
abstract::Efficient adaptation to iron starvation is an essential virulence determinant of the most common human mold pathogen, Aspergillus fumigatus. Here, we demonstrate that the cytosolic monothiol glutaredoxin GrxD plays an essential role in iron sensing in this fungus. Our studies revealed that (i) GrxD is essential for gr...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1008379
更新日期:2019-09-16 00:00:00
abstract::Mutational fitness effects can be measured with relatively high accuracy in viruses due to their small genome size, which facilitates full-length sequencing and genetic manipulation. Previous work has shown that animal and plant RNA viruses are very sensitive to mutation. Here, we characterize mutational fitness effec...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000742
更新日期:2009-11-01 00:00:00
abstract::Previous genetic studies have suggested a history of sub-Saharan African gene flow into some West Eurasian populations after the initial dispersal out of Africa that occurred at least 45,000 years ago. However, there has been no accurate characterization of the proportion of mixture, or of its date. We analyze genome-...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1001373
更新日期:2011-04-01 00:00:00
abstract::Meiotic recombination is essential for the repair of programmed double strand breaks (DSBs) to generate crossovers (COs) during meiosis. The efficient processing of meiotic recombination intermediates not only needs various resolvases but also requires proper meiotic chromosome structure. The Smc5/6 complex belongs to...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005872
更新日期:2016-03-24 00:00:00
abstract::Nutrient stresses trigger a variety of developmental switches in the budding yeast Saccharomyces cerevisiae. One of the least understood of such responses is the development of complex colony morphology, characterized by intricate, organized, and strain-specific patterns of colony growth and architecture. The genetic ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000823
更新日期:2010-01-22 00:00:00
abstract::Drosophila melanogaster head development represents a valuable process to study the developmental control of various organs, such as the antennae, the dorsal ocelli and the compound eyes from a common precursor, the eye-antennal imaginal disc. While the gene regulatory network underlying compound eye development has b...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1007180
更新日期:2018-01-23 00:00:00
abstract::Genetic studies have identified substantial non-African admixture in the Horn of Africa (HOA). In the most recent genomic studies, this non-African ancestry has been attributed to admixture with Middle Eastern populations during the last few thousand years. However, mitochondrial and Y chromosome data are suggestive o...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004393
更新日期:2014-06-12 00:00:00
abstract::The origin and evolution of new microRNAs (miRNAs) is important because they can impact the transcriptome broadly. As miRNAs can potentially emerge constantly and rapidly, their rates of birth and evolution have been extensively debated. However, most new miRNAs identified appear not to be biologically significant. Af...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004096
更新日期:2014-01-01 00:00:00
abstract::Seam cells in Caenorhabditis elegans provide a paradigm for the stem cell mode of division, with the ability to both self-renew and produce daughters that differentiate. The transcription factor RNT-1 and its DNA binding partner BRO-1 (homologues of the mammalian cancer-associated stem cell regulators RUNX and CBFβ, r...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1002200
更新日期:2011-08-01 00:00:00
abstract::Controlling infectious disease without inducing unwanted inflammatory disease requires proper regulation of the innate immune response. Thus, innate immunity needs to be activated when needed during an infection, but must be limited to prevent damage. To accomplish this, negative regulators of innate immunity limit th...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003855
更新日期:2013-10-01 00:00:00
abstract::Many diseases are differentially distributed among human populations. Differential selection on genetic variants in ancestral environments that coincidentally predispose to disease can be an underlying cause of these unequal prevalence patterns. Selected genes may be pleiotropic, affecting multiple phenotypes and resu...
journal_title:PLoS genetics
pub_type: 杂志文章,评审
doi:10.1371/journal.pgen.1005568
更新日期:2015-11-05 00:00:00
abstract::Phenylketonuria (PKU), one of the most common inherited diseases of amino acid metabolism, is caused by mutations in the phenylalanine hydroxylase (PAH) gene. Recently, PAH exon 11 was identified as a vulnerable exon due to a weak 3' splice site, with different exonic mutations affecting exon 11 splicing through disru...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1007360
更新日期:2018-04-23 00:00:00
abstract::Qsp1 is a secreted quorum sensing peptide required for virulence of the fungal meningitis pathogen Cryptococcus neoformans. Qsp1 functions to control cell wall integrity in vegetatively growing cells and also functions in mating. Rather than acting on a cell surface receptor, Qsp1 is imported to act intracellularly vi...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1008744
更新日期:2020-09-21 00:00:00
abstract::While several studies have investigated general properties of the genetic architecture of natural variation in gene expression, few of these have considered natural, outbreeding populations. In parallel, systems biology has established that a general feature of biological networks is that they are scale-free, renderin...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1006402
更新日期:2017-04-13 00:00:00
abstract::Traditional Chinese medicine (TCM) has been practiced for thousands of years, but only within the last few decades has its use become more widespread outside of Asia. Concerns continue to be raised about the efficacy, legality, and safety of many popular complementary alternative medicines, including TCMs. Ingredients...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1002657
更新日期:2012-01-01 00:00:00
abstract::Maintaining levels of calcium in the cytosol is important for many cellular events, including cell migration, where localized regions of high calcium are required to regulate cytoskeletal dynamics, contractility, and adhesion. Studies show inositol-trisphosphate receptors (IP3R) and ryanodine receptors (RyR), which re...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003506
更新日期:2013-05-01 00:00:00
abstract::Adipose tissue lipolysis occurs during the development of heart failure as a consequence of chronic adrenergic stimulation. However, the impact of enhanced adipose triacylglycerol hydrolysis mediated by adipose triglyceride lipase (ATGL) on cardiac function is unclear. To investigate the role of adipose tissue lipolys...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1007171
更新日期:2018-01-10 00:00:00
abstract::Genome-wide association studies have shown that pleiotropy is a common phenomenon that can potentially be exploited for enhanced detection of susceptibility loci. We propose heritability informed power optimization (HIPO) for conducting powerful pleiotropic analysis using summary-level association statistics. We find ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1007549
更新日期:2018-10-05 00:00:00
abstract::We have exploited the high selectivity of the homing endonuclease I-PpoI for the X-linked Anopheles gambiae 28S ribosomal genes to selectively target X chromosome carrying spermatozoa. Our data demonstrated that in heterozygous males, the expression of I-PpoI in the testes induced a strong bias toward Y chromosome-car...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000291
更新日期:2008-12-01 00:00:00
abstract::Ubiquitination of the replication clamp proliferating cell nuclear antigen (PCNA) at the conserved residue lysine (K)164 triggers postreplicative repair (PRR) to fill single-stranded gaps that result from stalled DNA polymerases. However, it has remained elusive as to whether cells engage PRR in response to replicatio...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005659
更新日期:2015-11-06 00:00:00
abstract::Little is known about contacts in the spliceosome between proteins and intron nucleotides surrounding the pre-mRNA branch-site and their dynamics during splicing. We investigated protein-pre-mRNA interactions by UV-induced crosslinking of purified yeast B(act) spliceosomes formed on site-specifically labeled pre-mRNA,...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005539
更新日期:2015-09-22 00:00:00