Decreased LIN28B in preeclampsia impairs human trophoblast differentiation and migration

Canfield, John; Arlıer, Sefa; Mong, Ezinne Francess; Lockhart, John H.; VanWye, Jeffrey; Guzeloglu‐Kayisli, Ozlem; Schatz, Frederick; Magness, Ronald R.; Lockwood, Charles J.; Tsibris, John C.M.; Kayisli, Umit A.; Totary-Jain, Hana

doi:10.1096/fj.201801163r

Cited by 54 publications

(65 citation statements)

References 71 publications

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“…To avoid the spontaneous differentiation of PHTs, in this study, we used undifferentiated iPSCs and found that 24 hours exposure to hypoxia (1% oxygen) significantly decreased the expression of numerous C19MC miRNAs and several reprogramming factors including OCT4 and LIN28B, whereas the expression of EMT related genes was increased. The repression of LIN28B expression in iPSCs by hypoxia agrees with our previous study that showed that hypoxia decreased the expression of LIN28B in choriocarcinoma BeWo and JEG3 cells, and in placentas from preeclampsia-affected pregnancies 40 . In addition, repression of OCT4 induces loss of pluripotency and differentiation of ESC cells derived from the inner cell mass toward the trophectoderm lineage 41 .…”

Section: Discussionsupporting

confidence: 91%

“…Immunohistochemistry. Cytokeratin and vimentin immunostaining of early human placental sections was performed as previously described 40,53 . Briefly, paraffin embedded sections were deparaffinized in xylene and rehydrated in a series of graded alcohol washes followed by antigen retrieval by boiling in citric acid (pH6.0).…”

Section: Methodsmentioning

confidence: 99%

“…For qRT-PCR analysis, 1 µg total RNA was reverse transcribed using random hexamer or oligodT primers and M-MuLV reverse transcriptase (New England Biolabs) according to the manufacturer's specifications. For miRNA cDNA, 0.5 ug of RNA was reverse transcribed using the TaqMan miRNA Reverse Transcription Kit (ThermoFisher Scientific, 4366596) as previously described 11,40 .…”

Section: Alkaline Phosphatase Staining Alkaline Phosphatase Histochementioning

confidence: 99%

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Chromosome 19 microRNA cluster enhances cell reprogramming by inhibiting epithelial-to-mesenchymal transition

Mong

Yang

Akat

et al. 2020

Sci Rep

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During implantation, cytotrophoblasts undergo epithelial-to-mesenchymal transition (EMT) as they differentiate into invasive extravillous trophoblasts (EVTs). The primate-specific microRNA cluster on chromosome 19 (C19MC) is exclusively expressed in the placenta, embryonic stem cells and certain cancers however, its role in EMT gene regulation is unknown. In situ hybridization for miR-517a/c, a C19MC cistron microRNA, in first trimester human placentas displayed strong expression in villous trophoblasts and a gradual decrease from proximal to distal cell columns as cytotrophoblasts differentiate into invasive EVTs. To investigate the role of C19MC in the regulation of EMT genes, we employed the CRISPR/dCas9 Synergistic Activation Mediator (SAM) system, which induced robust transcriptional activation of the entire C19MC cistron and resulted in suppression of EMT associated genes. Exposure of human iPSCs to hypoxia or differentiation of iPSCs into either cytotrophoblaststem-like cells or EVT-like cells under hypoxia reduced C19MC expression and increased EMT genes. Furthermore, transcriptional activation of the C19MC cistron induced the expression of OCT4 and FGF4 and accelerated cellular reprogramming. This study establishes the CRISPR/dCas9 SAM as a powerful tool that enables activation of the entire C19MC cistron and uncovers its novel role in suppressing EMT genes critical for maintaining the epithelial cytotrophoblasts stem cell phenotype.Human embryonic implantation into the uterus requires extensive coordinated attachment and invasion of the maternal endometrium by fetal trophoblasts. While in the fallopian tube, the developing embryo differentiates into the blastocyst, which consists of an inner cell mass, destined to become the fetus, and the trophectoderm, an outer layer of epithelial cells that eventually develops into the placenta 1 . Shortly before implantation, the highly mitotic cells derived from the trophectoderm -the cytotrophoblast (CTs) -differentiate into either multinucleated syncytiotrophoblast (STs) or extravillous trophoblast (EVTs). STs form the outer villous layer of the placenta and regulate maternal-fetal gas exchange, nutrient uptake and waste elimination. The interstitial EVTs invade the decidua and inner myometrium to anchor the chorionic villi to the decidua and uterine wall. Concurrently, endovascular EVTs penetrate the maternal spiral arteries and participate in remodeling them into high-flow, low-resistance vessels that facilitate placental perfusion to accommodate increasing O 2 and nutrient demands by the developing fetus 2,3 .In humans, EVT differentiation and invasion are crucial steps involved in implantation and placentation. These cellular processes are regulated by several molecular mechanisms, which have not been completely elucidated. Inadequate EVT invasion, so called shallow placentation, can elicit placental hypoperfusion resulting in pregnancy complications including fetal loss, preeclampsia and/or fetal growth restriction 4,5 . In contrast increased EVT invasion ca...

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Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Alkaline Phosphatase Staining Alkaline Phosphatase Histochementioning

confidence: 99%

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Chromosome 19 microRNA cluster enhances cell reprogramming by inhibiting epithelial-to-mesenchymal transition

Mong

Yang

Akat

et al. 2020

Sci Rep

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“…Because then, we found that LIN28B in fact is the predominant LIN28 homolog expressed in human first‐trimester placenta, localized to the cytotrophoblast cells, and present in commonly used human trophoblast cell lines (West et al, ). This was also recently confirmed by Canfield et al (). Similar to LIN28B, AR is not present in the differentiated syncytiotrophoblast layer, which is positive for hCG, but appears to localize to trophoblast cells right beneath the syncytiotrophoblast layer.…”

Section: Discussionsupporting

confidence: 81%

“…Contrary to mice, human trophoblast cells primarily express LIN28B (Canfield et al, 2018;West et al, 2018), and in this study we explored the possibility that androgen receptor (AR) is a potential target for LIN28B. AR localizes to villous stromal cells, cytotrophoblast, and syncytiotrophoblast in term placenta (Iwamura, Abrahamsson, Benning, Cockett, & di Sant'Agnese, 1994;Horie, Takakura, Imai, Liao, & Mori, 1992), and previous work in our lab suggests AR is involved in regulating placental angiogenesis through its interaction with VEGFA during pregnancy (Cleys et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

LIN28B regulates androgen receptor in human trophoblast cells through Let‐7c

McWhorter

West

Russ

et al. 2019

Molecular Reproduction Devel

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LIN28B is an RNA‐binding protein necessary for maintaining pluripotency in stem cells and plays an important role in trophoblast cell differentiation. LIN28B action on target gene function often involves the Let‐7 miRNA family. Previous work in cancer cells revealed that LIN28 through Let‐7 miRNA regulates expression of androgen receptor (AR). Considering the similarities between cancer and trophoblast cells, we hypothesize that LIN28B also is necessary for the presence of AR in human trophoblast cells. The human first‐trimester trophoblast cell line, ACH‐3P was used to evaluate the regulation of AR by LIN28B, and a LIN28B knockdown cell line was constructed using lentiviral‐based vectors. LIN28B knockdown in ACH‐3P cells resulted in significantly decreased levels of AR and increased levels of Let‐7 miRNAs. Moreover, treatment of ACH‐3P cells with Let‐7c mimic, but not Let‐7e or Let‐7f, resulted in a significant reduction in LIN28B and AR. Finally, forskolin‐induced syncytialization and Let‐7c treatment both resulted in increased expression of syncytiotrophoblast marker ERVW‐1 and a significant decrease in AR in ACH‐3P. These data reveal that LIN28B regulates AR levels in trophoblast cells likely through its inhibitory actions on let‐7c, which may be necessary for trophoblast cell differentiation into the syncytiotrophoblast.

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The transposable element-derived transcript of LIN28B has a placental origin and is not specific to tumours

et al. 2023

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Transposable elements (TEs) are genetic elements that have evolved as crucial regulators of human development and cancer, functioning as both genes and regulatory elements. When TEs become dysregulated in cancer cells, they can serve as alternate promoters to activate oncogenes, a process known as onco-exaptation. This study aimed to explore the expression and epigenetic regulation of onco-exaptation events in early human developmental tissues. We discovered co-expression of some TEs and oncogenes in human embryonic stem cells and first trimester and term placental tissues. Previous studies identified onco-exaptation events in various cancer types, including an AluJb SINE element–LIN28B interaction in lung cancer cells, and showed that the TE-derived LIN28B transcript is associated with poor patient prognosis in hepatocellular carcinoma. This study further characterized the AluJb–LIN28B transcript and confirmed that its expression is restricted to the placenta. Targeted DNA methylation analysis revealed differential methylation of the two LIN28B promoters between placenta and healthy somatic tissues, indicating that some TE–oncogene interactions are not cancer-specific but arise from the epigenetic reactivation of developmental TE-derived regulatory events. In conclusion, our findings provide evidence that some TE–oncogene interactions are not limited to cancer and may originate from the epigenetic reactivation of TE-derived regulatory events that are involved in early development. These insights broaden our understanding of the role of TEs in gene regulation and suggest the potential importance of targeting TEs in cancer therapy beyond their conventional use as cancer-specific markers.

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Decreased LIN28B in preeclampsia impairs human trophoblast differentiation and migration

Cited by 54 publications

References 71 publications

Chromosome 19 microRNA cluster enhances cell reprogramming by inhibiting epithelial-to-mesenchymal transition

Chromosome 19 microRNA cluster enhances cell reprogramming by inhibiting epithelial-to-mesenchymal transition

LIN28B regulates androgen receptor in human trophoblast cells through Let‐7c

The transposable element-derived transcript of LIN28B has a placental origin and is not specific to tumours

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