The Transcription Factor Elf3 Is Essential for a Successful Mesenchymal to Epithelial Transition

Sengez, Burcu; Aygün, Ilkin; Shehwana, Huma; Toyran, Neslihan; Avcı, Sanem Tercan; Konu, Özlen; Stemmler, Marc P.; Alotaibi, Hani

doi:10.3390/cells8080858

Cited by 33 publications

(28 citation statements)

References 82 publications

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“…REL promotes expression of CBP and HDAC6 co-regulated TFs. Our findings are supported by in silico predictions suggesting that Rel expression correlates with Cdh1 expression 40 . One mechanism by which REL induces MET is through repression of Hdac6 where REL binds the Hdac6 promoter in TS WT cells.…”

Section: Discussionsupporting

confidence: 85%

Coordinated regulation of Rel expression by MAP3K4, CBP, and HDAC6 controls phenotypic switching

et al. 2020

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Coordinated gene expression is required for phenotypic switching between epithelial and mesenchymal phenotypes during normal development and in disease states. Trophoblast stem (TS) cells undergo epithelial-mesenchymal transition (EMT) during implantation and placentation. Mechanisms coordinating gene expression during these processes are poorly understood. We have previously demonstrated that MAP3K4-regulated chromatin modifiers CBP and HDAC6 each regulate thousands of genes during EMT in TS cells. Here we show that CBP and HDAC6 coordinate expression of only 183 genes predicted to be critical regulators of phenotypic switching. The highest-ranking co-regulated gene is the NF-κB family member Rel. Although NF-κB is primarily regulated post-transcriptionally, CBP and HDAC6 control Rel transcript levels by binding Rel regulatory regions and controlling histone acetylation. REL re-expression in mesenchymal-like TS cells induces a mesenchymal-epithelial transition. Importantly, REL forms a feedback loop, blocking HDAC6 expression and nuclear localization. Together, our work defines a developmental program coordinating phenotypic switching.

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Section: Discussionsupporting

confidence: 85%

Coordinated regulation of Rel expression by MAP3K4, CBP, and HDAC6 controls phenotypic switching

et al. 2020

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“…These genes showed no coding region acceleration, which is expected since they are highly pleiotropic. Regulatory proteins tend to have many functions – for example, in addition to their hair-related functions, FOXC1 regulates embryonic development (Brembeck, Opitz, Libermann, & Rustgi, 2000; Seo et al, 2006) and ELF3 is involved in the epithelial to mesenchymal transition (Sengez et al, 2019) – so we expected to observe no loss of constraint in the coding sequence for those proteins. Instead, changes to regions that regulate expression of those regulatory proteins appear to be driving the convergent evolution of hairlessness.…”

Section: Resultsmentioning

confidence: 99%

“…In fact, among the top-ranked non-keratin genes with quickly evolving nearby noncoding regions, only one gene showed a significant evolutionary rate shift in protein-coding sequence (Figure 6). FOXC1 and ELF3 , among the top-ranked genes, are strongly linked to hair and skin development (Brembeck et al, 2000; Lay et al, 2016; L. Wang et al, 2016) but also have other essential functions (Aldinger et al, 2009; Sengez et al, 2019; Seo et al, 2006). Our findings imply that many hair-related genes may have similar pleiotropy preventing accelerated evolution of coding sequence in hairless species.…”

Section: Discussionmentioning

confidence: 99%

Complementary evolution of coding and noncoding sequence underlies mammalian hairlessness

Kowalczyk

Chikina

Clark

2021

Preprint

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Body hair is a defining mammalian characteristic, but several mammals, such as whales, naked mole-rats, and humans, have notably less hair than others. To find the genetic basis of reduced hair quantity, we used our evolutionary-rates-based method, RERconverge, to identify coding and noncoding sequences that evolve at significantly different rates in so-called hairless mammals compared to hairy mammals. Using RERconverge, we performed an unbiased, genome-wide scan over 62 mammal species using 19,149 genes and 343,598 conserved noncoding regions to find genetic elements that evolve at significantly different rates in hairless mammals compared to hairy mammals. We show that these rate shifts resulted from relaxation of evolutionary constraint on hair-related sequences in hairless species. In addition to detecting known and potential novel hair-related genes, we also discovered hundreds of putative hair-related regulatory elements. Computational investigation revealed that genes and their associated noncoding regions show different evolutionary patterns and influence different aspects of hair growth and development. Many genes under accelerated evolution are associated with the structure of the hair shaft itself, while evolutionary rate shifts in noncoding regions also included the dermal papilla and matrix regions of the hair follicle that contribute to hair growth and cycling. Genes that were top-ranked for coding sequence acceleration included known hair and skin genes KRT2, KRT35, PKP1, and PTPRM that surprisingly showed no signals of evolutionary rate shifts in nearby noncoding regions. Conversely, accelerated noncoding regions are most strongly enriched near regulatory hair-related genes and microRNAs, such as mir205, ELF3, and FOXC1, that themselves do not show rate shifts in their protein-coding sequences. Such dichotomy highlights the interplay between the evolution of protein sequence and regulatory sequence to contribute to the emergence of a convergent phenotype.

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“…More recently, ELF3 has been implicated in maintaining cell identity. Knockdown of ELF3 in keratinocytes resulted in an epithelial-to-mesenchymal transition (EMT) ( 45 ). It is thus conceivable that the autoregulatory feedback loop that reinforces high ELF3 expression might therefore be involved in maintaining trophectoderm identity, a process described in several model organisms and cell lines ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

ELF3 activated by a superenhancer and an autoregulatory feedback loop is required for high-level HLA-C expression on extravillous trophoblasts

Meißner

Wang

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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HLA-C arose during evolution of pregnancy in the great apes 10 to 15 million years ago. It has a dual function on placental extravillous trophoblasts (EVTs) as it contributes to both tolerance and immunity at the maternal–fetal interface. The mode of its regulation is of considerable interest in connection with the biology of pregnancy and pregnancy abnormalities. First-trimester primary EVTs in which HLA-C is highly expressed, as well as JEG3, an EVT model cell line, were employed. Single-cell RNA-seq data and quantitative PCR identified high expression of the transcription factor ELF3 in those cells. Chromatin immunoprecipitation (ChIP)-PCR confirmed that both ELF3 and MED1 bound to the proximal HLA-C promoter region. However, binding of RFX5 to this region was absent or severely reduced, and the adjacent HLA-B locus remained closed. Expression of HLA-C was inhibited by ELF3 small interfering RNAs (siRNAs) and by wrenchnolol treatment. Wrenchnolol is a cell-permeable synthetic organic molecule that mimics ELF3 and is relatively specific for binding to ELF3’s coactivator, MED23, as our data also showed in JEG3. Moreover, the ELF3 gene is regulated by a superenhancer that spans more than 5 Mb, identified by assay for transposase-accessible chromatin using sequencing (ATAC-seq), as well as by its sensitivity to (+)-JQ1 (inhibitor of BRD4). ELF3 bound to its own promoter, thus creating an autoregulatory feedback loop that establishes expression of ELF3 and HLA-C in trophoblasts. Wrenchnolol blocked binding of MED23 to ELF3, thus disrupting the positive-feedback loop that drives ELF3 expression, with down-regulation of HLA-C expression as a consequence.

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The Transcription Factor Elf3 Is Essential for a Successful Mesenchymal to Epithelial Transition

Cited by 33 publications

References 82 publications

Coordinated regulation of Rel expression by MAP3K4, CBP, and HDAC6 controls phenotypic switching

Coordinated regulation of Rel expression by MAP3K4, CBP, and HDAC6 controls phenotypic switching

Complementary evolution of coding and noncoding sequence underlies mammalian hairlessness

ELF3 activated by a superenhancer and an autoregulatory feedback loop is required for high-level HLA-C expression on extravillous trophoblasts

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