Abstract:PAIRED (PRD)-like homeobox genes belong to a class of predicted transcription factor genes. Several of these PRD-like homeobox genes have been predicted in silico from genomic sequence but until recently had no evidence of transcript expression. We found recently that nine PRD-like homeobox genes, ARGFX, CPHX1, CPHX2, DPRX, DUXA, DUXB, NOBOX, TPRX1 and TPRX2, were expressed in human preimplantation embryos. In the current study we characterized these PRD-like homeobox genes in depth and studied their functions… Show more
“…Several homeobox genes have already been described as characteristic of one or more of these tissues or developmental stages, and these are found in our list. Examples include NANOG and POU5F1 which are well-characterised markers of pluripotent cells and several totipotent-cell expressed PRD class genes that have been the focus of recent functional studies ( ARGFX, CPHX1, CPHX2, DPRX, LEUTX, TPRX1, TPRX2, OTX1, OTX2 ) [19, 20]. Interestingly, many other homeobox genes also cluster in this set on the basis of their expression, including two Hox genes ( HOXD1, HOXC13 ) indicating they are worthy of further study in this regard (Additional file 5: Table S6).…”
Section: Resultsmentioning
confidence: 99%
“…The peak of 8-cell to morula suggests these genes may combine to prepare the totipotent stages of embryonic development for subsequent cell fate specialisation. Indeed, two recent studies have postulated regulatory roles for several of these genes during early human embryo development [19, 20]. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Classification of human homeobox genes followed Zhong and Holland [2], based on Holland et al [1], except that CPHX1 and CPHX2 are here placed in the PRD class following Töhönen et al [17]. NANOGNB is here provisionally considered in the ANTP class on the basis of chromosomal location, TPRX2 is considered a functional gene rather than a pseudogene [19, 20], and DUX loci are restricted to DUXA , DUXB and DUX4. …”
BackgroundHomeobox genes encode a diverse set of transcription factors implicated in a vast range of biological processes including, but not limited to, embryonic cell fate specification and patterning. Although numerous studies report expression of particular sets of homeobox genes, a systematic analysis of the tissue specificity of homeobox genes is lacking.ResultsHere we analyse publicly-available transcriptome data from human and mouse developmental stages, and adult human tissues, to identify groups of homeobox genes with similar expression patterns. We calculate expression profiles for 242 human and 278 mouse homeobox loci across a combination of 59 human and 12 mouse adult tissues, early and late developmental stages. This revealed 20 human homeobox genes with widespread expression, primarily from the TALE, CERS and ZF classes. Most homeobox genes, however, have greater tissue-specificity, allowing us to compile homeobox gene expression lists for neural tissues, immune tissues, reproductive and developmental samples, and for numerous organ systems. In mouse development, we propose four distinct phases of homeobox gene expression: oocyte to zygote; 2-cell; 4-cell to blastocyst; early to mid post-implantation. The final phase change is marked by expression of ANTP class genes. We also use these data to compare expression specificity between evolutionarily-based gene classes, revealing that ANTP, PRD, LIM and POU homeobox gene classes have highest tissue specificity while HNF, TALE, CUT and CERS are most widely expressed.ConclusionsThe homeobox genes comprise a large superclass and their expression patterns are correspondingly diverse, although in a broad sense related to an evolutionarily-based classification. The ubiquitous expression of some genes suggests roles in general cellular processes; in contrast, most human homeobox genes have greater tissue specificity and we compile useful homeobox datasets for particular tissues, organs and developmental stages. The identification of a set of eutherian-specific homeobox genes peaking from human 8-cell to morula stages suggests co-option of new genes to new developmental roles in evolution.Electronic supplementary materialThe online version of this article (doi:10.1186/s12861-016-0140-y) contains supplementary material, which is available to authorized users.
“…Several homeobox genes have already been described as characteristic of one or more of these tissues or developmental stages, and these are found in our list. Examples include NANOG and POU5F1 which are well-characterised markers of pluripotent cells and several totipotent-cell expressed PRD class genes that have been the focus of recent functional studies ( ARGFX, CPHX1, CPHX2, DPRX, LEUTX, TPRX1, TPRX2, OTX1, OTX2 ) [19, 20]. Interestingly, many other homeobox genes also cluster in this set on the basis of their expression, including two Hox genes ( HOXD1, HOXC13 ) indicating they are worthy of further study in this regard (Additional file 5: Table S6).…”
Section: Resultsmentioning
confidence: 99%
“…The peak of 8-cell to morula suggests these genes may combine to prepare the totipotent stages of embryonic development for subsequent cell fate specialisation. Indeed, two recent studies have postulated regulatory roles for several of these genes during early human embryo development [19, 20]. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Classification of human homeobox genes followed Zhong and Holland [2], based on Holland et al [1], except that CPHX1 and CPHX2 are here placed in the PRD class following Töhönen et al [17]. NANOGNB is here provisionally considered in the ANTP class on the basis of chromosomal location, TPRX2 is considered a functional gene rather than a pseudogene [19, 20], and DUX loci are restricted to DUXA , DUXB and DUX4. …”
BackgroundHomeobox genes encode a diverse set of transcription factors implicated in a vast range of biological processes including, but not limited to, embryonic cell fate specification and patterning. Although numerous studies report expression of particular sets of homeobox genes, a systematic analysis of the tissue specificity of homeobox genes is lacking.ResultsHere we analyse publicly-available transcriptome data from human and mouse developmental stages, and adult human tissues, to identify groups of homeobox genes with similar expression patterns. We calculate expression profiles for 242 human and 278 mouse homeobox loci across a combination of 59 human and 12 mouse adult tissues, early and late developmental stages. This revealed 20 human homeobox genes with widespread expression, primarily from the TALE, CERS and ZF classes. Most homeobox genes, however, have greater tissue-specificity, allowing us to compile homeobox gene expression lists for neural tissues, immune tissues, reproductive and developmental samples, and for numerous organ systems. In mouse development, we propose four distinct phases of homeobox gene expression: oocyte to zygote; 2-cell; 4-cell to blastocyst; early to mid post-implantation. The final phase change is marked by expression of ANTP class genes. We also use these data to compare expression specificity between evolutionarily-based gene classes, revealing that ANTP, PRD, LIM and POU homeobox gene classes have highest tissue specificity while HNF, TALE, CUT and CERS are most widely expressed.ConclusionsThe homeobox genes comprise a large superclass and their expression patterns are correspondingly diverse, although in a broad sense related to an evolutionarily-based classification. The ubiquitous expression of some genes suggests roles in general cellular processes; in contrast, most human homeobox genes have greater tissue specificity and we compile useful homeobox datasets for particular tissues, organs and developmental stages. The identification of a set of eutherian-specific homeobox genes peaking from human 8-cell to morula stages suggests co-option of new genes to new developmental roles in evolution.Electronic supplementary materialThe online version of this article (doi:10.1186/s12861-016-0140-y) contains supplementary material, which is available to authorized users.
“…Therefore, the opening of these elements, or interference with their function, may contribute to more efficient activation of nearby genes by interfering with chromatin insulation. Further insight into the mechanisms will require characterisation of factors binding to the motif during reprogramming as well as characterization of the function of early embryo factors, which are known to target the motif, e.g., PRD-like totipotent cell homeodomain factors and HNF4a 31,[39][40][41][42] .…”
CRISPR/Cas9 based gene activation (CRISPRa) is an attractive tool for cellular reprogramming applications due to its high multiplexing capacity and direct targeting of endogenous loci. Here we present the reprogramming of primary human skin fibroblasts into induced pluripotent stem cells (iPSC) using CRISPRa, targeting endogenous OCT4, SOX2, KLF4, MYC and LIN28A promoters. The basal reprogramming efficiency can be improved by an order of magnitude by additionally targeting a conserved Alu-motif, enriched near genes involved in embryo genome activation (EEA-motif). This effect is mediated in part by more efficient activation of NANOG and REX1. These data constitute a proof of principle that somatic cells can be reprogrammed into iPSC using only CRISPRa. Furthermore, the results unravel previously uncharacterized involvement of EEA-motif-associated mechanisms in cellular reprogramming.
“…26,27 Furthermore, it has been shown that in healthy tissue the expressed genes, lncRNAs, and pseudogenes of the DUX homeobox family function in transcriptional regulation mostly by repressing expression of hundreds of target genes associated with maintaining the differentiation status of somatic cells, thus indirectly promoting a dedifferentiation state related to early embryonal development. 12,13 Therefore, the DUX transcriptional regulators complement the HOX transcription factors, which can directly activate genes driving or supporting cellular dedifferentiation, known from embryonal development. Based on this information, it is easily conceivable that the transformation from papilloma to Schneiderian SNSCC is characterized on the molecular level mostly by the emerging and changing activation of the HOX genes presented here, together with the late appearance of the DUX genes and DUX lncRNAs to evolve to stable cancer stem cells.…”
Background
Sinonasal papilloma has a tendency toward local destruction, recurrence, and malignant transformation. This study aimed to unravel mechanisms in the malignant transformation of sinonasal papillomas using RNA‐seq.
Methods
The cohort consisted of 37 consecutive patients; tumor histology included a continuum spectrum (sinonasal papillomas/dysplastic/carcinomas‐in‐situ/invasive squamous cell carcinomas). These were microdissected and RNA was subjected to whole‐transcriptome shotgun sequencing.
Results
RNA‐seq and pathway analysis showed that the highest expressed genes/potential drivers were development‐ and differentiation‐related genes. The protein expression of six highly upregulated genes (HOXA9, EN1, DUX4, CA9, CD1a, and CK5/6) validated the RNA‐seq results. HOXA9 and CA9 were found to be expressed in most of the carcinoma samples but were largely negative in papillomas; all of the CA9‐negative carcinomas were recurrent.
Conclusions
We conclude that sinonasal carcinomas arising from papillomas are mainly defined by overexpressed developmental/homeobox genes, which provide the potential for transformation/plasticity, along with differentiation and proliferation behavior of neoplastic cells. Our results support HOXA9 and CA9 as biomarkers for carcinomas, with CA9 emerging as a predictive marker of recurrence.
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