KLF4 protein stability regulated by interaction with pluripotency transcription factors overrides transcriptional control

Dhaliwal, Navroop K.; Abatti, Luis E.; Mitchell, Jennifer A.

doi:10.1101/gad.324319.119

Cited by 30 publications

(34 citation statements)

References 62 publications

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“…KLF4 could block SE for differentiation into differentiated types of NSGCT, TER, YST, and CC. RNA expression of KLF4 had a longer half-life when the cells expressed NANOG and POU5F1 [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Meta-Analysis of Gene Expressions in Testicular Germ Cell Tumor Histologies

Eyben

Parraga-Alava

2020

IJMS

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There is no consensus as to how a precursor lesion, germ cell neoplasia in situ (GCNIS), develops into the histologic types of testicular germ cell tumor type II (TGCT). The present meta-analysis examined RNA expressions of 24 candidate genes in three datasets. They included 203 samples of normal testis (NT) and histologic types of TGCT. The Fisher’s test for combined p values was used for meta-analysis of the RNA expressions in the three datasets. The histologic types differed in RNA expression of PRAME, KIT, SOX17, NANOG, KLF4, POU5F1, RB1, DNMT3B, and LIN28A (p < 0.01). The histologic types had concordant differences in RNA expression of the genes in the three datasets. Eight genes had overlap with a high RNA expression in at least two histologic types. In contrast, only seminoma (SE) had a high RNA expression of KLF4 and only embryonal carcinoma (EC) had a high RNA expression of DNMT3B. In conclusion, the meta-analysis showed that the development of the histologic types of TGCT was driven by changes in RNA expression of candidate genes. According to the RNA expressions of the ten genes, TGCT develops from NT over GCNIS, SE, EC, to the differentiated types of TGCT.

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Section: Discussionmentioning

confidence: 99%

Meta-Analysis of Gene Expressions in Testicular Germ Cell Tumor Histologies

Eyben

Parraga-Alava

2020

IJMS

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“…In NOMO-1 NANOG activated KLF4 but KLF4 did not influence the expression of NANOG in return. This observation contrasts ESCs in which NANOG activates KLF4 transcription and interacts with the encoded protein for stabilization [87]. KLF4 performs both stem cell maintenance and monocyte differentiation and may thus play dual roles in AML cells [40,88].…”

Section: Discussionmentioning

confidence: 99%

NKL homeobox gene activities in normal and malignant myeloid cells

Nagel¹,

Scherr²,

MacLeod³

et al. 2019

PLoS ONE

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Recently, we have documented a hematopoietic NKL-code mapping physiological expression patterns of NKL homeobox genes in early hematopoiesis and in lymphopoiesis, which spotlights genes deregulated in lymphoid malignancies. Here, we enlarge this map to include normal NKL homeobox gene expressions in myelopoiesis by analyzing public expression profiling data and primary samples from developing and mature myeloid cells. We thus uncovered differential activities of six NKL homeobox genes, namely DLX2, HHEX, HLX, HMX1, NKX3-1 and VENTX. We further examined public expression profiling data of 251 acute myeloid leukemia (AML) and 183 myelodysplastic syndrome (MDS) patients, thereby identifying 24 deregulated genes. These results revealed frequent deregulation of NKL homeobox genes in myeloid malignancies. For detailed analysis we focused on NKL homeobox gene NANOG, which acts as a stem cell factor and is correspondingly expressed alone in hematopoietic progenitor cells. We detected aberrant expression of NANOG in a small subset of AML patients and in AML cell line NOMO-1, which served as a model. Karyotyping and genomic profiling discounted rearrangements of the NANOG locus at 12p13. But gene expression analyses of AML patients and AML cell lines after knockdown and overexpression of NANOG revealed regulators and target genes. Accordingly, NKL homeobox genes HHEX, DLX5 and DLX6, stem cell factors STAT3 and TET2, and the NOTCH-pathway were located upstream of NANOG while NKL homeobox genes HLX and VENTX, transcription factors KLF4 and MYB, and anti-apoptosis-factor MIR17HG represented target genes. In conclusion, we have extended the NKL-code to the myeloid lineage and thus identified several NKL homeobox genes deregulated in AML and MDS. These data indicate a common oncogenic role of NKL homeobox genes in both lymphoid and myeloid malignancies. For misexpressed NANOG we identified an aberrant regulatory network, which contributes to the understanding of the oncogenic activity of NKL homeobox genes.

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“…Apart from varying of levels of primary transcript generation in the nucleus, these mechanisms can include nuclear retention of processed mRNA [24,25], alternative splicing [26,27], and increased mRNA stability [28,29]. Furthermore, multiple gene activation and repression mechanisms can compete to determine the expression outcome of a particular gene, as demonstrated by select biological contexts in which there is an imperfect correlation between the levels of a gene's transcribed and its translated products [30].…”

Section: Up-regulation Of Labor-associated Genes Involves a Transcripmentioning

confidence: 99%

The pregnant myometrium is epigenetically activated at contractility-driving gene loci prior to the onset of labor in mice

et al. 2020

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During gestation, uterine smooth muscle cells transition from a state of quiescence to one of contractility, but the molecular mechanisms underlying this transition at a genomic level are not well-known. To better understand these events, we evaluated the epigenetic landscape of the mouse myometrium during the pregnant, laboring, and postpartum stages. We generated gestational time point-specific enrichment profiles for histone H3 acetylation on lysine residue 27 (H3K27ac), histone H3 trimethylation of lysine residue 4 (H3K4me3), and RNA polymerase II (RNAPII) occupancy by chromatin immunoprecipitation with massively parallel sequencing (ChIP-seq), as well as gene expression profiles by total RNA-sequencing (RNA-seq). Our findings reveal that 533 genes, including known contractility-driving genes (Gap junction alpha 1 [Gja1], FBJ osteosarcoma oncogene [Fos], Fos-like antigen 2 [Fosl2], Oxytocin receptor [Oxtr], and Prostaglandin G/H synthase 2 (Ptgs2), for example), are upregulated at day 19 during active labor because of an increase in transcription at gene bodies. Labor-associated promoters and putative intergenic enhancers, however, are epigenetically activated as early as day 15, by which point the majority of genome-wide H3K27ac or H3K4me3 peaks present in term laboring tissue is already established. Despite this early exhibited histone signature, increased noncoding enhancer RNA (eRNA) production at putative intergenic enhancers and recruitment of RNAPII to the gene bodies of labor-associated loci were detected only during labor. Our findings indicate that epigenetic activation of the myometrial genome precedes active labor by at least 4 days in the mouse model, suggesting that the myometrium is poised for rapid activation of contraction-associated genes in order to exit the state of quiescence.

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KLF4 protein stability regulated by interaction with pluripotency transcription factors overrides transcriptional control

Cited by 30 publications

References 62 publications

Meta-Analysis of Gene Expressions in Testicular Germ Cell Tumor Histologies

Meta-Analysis of Gene Expressions in Testicular Germ Cell Tumor Histologies

NKL homeobox gene activities in normal and malignant myeloid cells

The pregnant myometrium is epigenetically activated at contractility-driving gene loci prior to the onset of labor in mice

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