The transcription factor HAND2 up-regulates transcription of the IL15 gene in human endometrial stromal cells

Murata, Hiromi; Tanaka, Susumu; Tsuzuki‐Nakao, Tomoko; Kido, Takeharu; Kakita‐Kobayashi, Maiko; Kida, Naoko; Hisamatsu, Yoji; Tsubokura, Hiroaki; Hashimoto, Yoshiko; Kitada, Masaaki; Okada, Hidetaka

doi:10.1074/jbc.ra120.012753

Cited by 40 publications

(48 citation statements)

References 43 publications

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“…In addition, we extracted and analyzed all the genes in the MEturquoise module and found five important genes ( HAND2 , LMO1 , MYH11 , MYLK and FHL1 ) which accounted for a significantly higher proportion in the IM-H subtype. HAND2 can regulates interleukin 15 (IL15), a key immune factor required for the activation and survival of uterine natural killer (uNK) cells [ 41 ]. LMO1 overexpression in GC could be as one of new markers of poor prognosis [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Classification of gastric cancers based on immunogenomic profiling

Liu

Jiang

et al. 2021

Translational Oncology

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Background Extensive evidence showed that gastric cancer (GC) is heterogeneous, and many studies have been focused on identifying GC subtypes based on genomic profiles. However, few studies have specifically explored the GC classification and predicted the classification accuracy that may help facilitate the optimal stratification of GC patients responsive to immunotherapy. Methods Using two publicly available GC genomics datasets, we classified GC on the basis of 797 immune related genes. Unsupervised and supervised machine learning methods were used to predict the classification. Results We identified two GC subtypes that we named as Immunity-High (IM-H) and Immunity- Low (IM-L), and demonstrated that this classification was duplicable and predictable by analyzing other datasets. IM-H subtype was characterized by greater immune cell infiltration, stronger immune activities, lower tumor purity, as well as worse survival prognosis compared to IM-L subtype. Besides the immune signatures, some cancer-associated pathways were hyperactivated in IM-H, including TGF-beta signaling pathway, Focal adhesion, Cell adhesion molecules (CAMs), Calcium signaling pathway, mTOR signaling pathway, MAPK signaling pathway and Wnt signaling pathway. In contrast, IM-L presented depressed immune signatures and increased activation of base excision repair, DNA replication, homologous recombination, non-homologous end-joining and nucleotide excision repair pathways. Furthermore, we identified subtype-specific genomic or clinical features, and subtype-specific gene ontology and networks in IM-H and IM-L subtype. Conclusions We proposed and validated two reproducible immune molecular subtypes of GC, which has potential clinical implications for GC patient selection of immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Classification of gastric cancers based on immunogenomic profiling

Liu

Jiang

et al. 2021

Translational Oncology

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“…We found that, like HAND2, IL15 decreases throughout gestation and both genes increase in expression as the menstrual cycle progresses. Unexpectedly however, while previous studies showed that HAND2 induces IL15 in DSCs (Shindoh et al ., 2014; Murata et al ., 2020), we discovered that HAND2 inhibited IL15 expression in ESFs, indicating a switch in regulatory activity sometime during early menstrual cycle. These data suggest that HAND2 regulates the appropriate timing of endometrial IL15 expression during the menstrual cycle and pregnancy, and thus the appropriate timing of uNK cell recruitment, trophoblast migration and the clearance of senescent endometrial stromal cells from the implantation site ( Figure 5D ).…”

Section: Discussionmentioning

confidence: 99%

Evolutionary transcriptomics implicatesHAND2in the origins of implantation and regulation of gestation length

Marinić

Mika

Chigurupati

et al. 2020

Preprint

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The developmental origins and evolutionary histories of cell types, tissues and organ systems contribute to the ways in which their dysfunction leads to disease. In mammals for example, the nature and extent of maternal-fetal interactions, how those interactions develop, and their evolutionary history likely influence diseases of pregnancy such as infertility and preterm birth.Here we show genes that evolved to be expressed at the maternal-fetal interface in Eutherian (Placental) mammals play essential roles in the evolution of pregnancy and are associated with immune system disorders and preterm birth. Among these genes is the transcription factor HAND2, which suppresses estrogen signaling thereby allowing blastocyst implantation, indicating that the suppression of estrogen signaling during pregnancy is an innovation of Eutherian mammals. We found that HAND2 is dynamically expressed in the decidua throughout the menstrual cycle and pregnancy, gradually decreasing to reach a low at term. HAND2 regulates a small but distinct set of target genes in endometrial stromal fibroblasts including the cytokine IL15, which was also dynamically expressed throughout the menstrual cycle and gestation, and promoted the migration of natural killer cells and extravillous cytotrophoblasts.Remarkably, we found that the HAND2 promoter loops to a distal enhancer containing SNPs implicated in the regulation of gestation length and birth weight. Collectively, these data implicate HAND2 expression at the maternal-fetal interface, with the evolution of implantation and gestation length regulation, and preterm birth.

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“…Decidualization is driven by increases in P4 and then local cyclic adenosine monophosphate (cAMP) production [ 8 , 9 ]. In the human endometrium after ovulation, ESCs transform from fibroblast-like cells in the proliferative phase to epithelium-like cells with cytoplasmic expansion, large pale nuclei, and rounded shapes in the secretory phase [ 10 ] ( Figure 1 ), a process that involves complex cytoskeletal rearrangements [ 11 ]. The phosphorylation of myosin light chain and concentrated F-actin induce the intracellular remodeling and resulting morphological changes [ 12 , 13 , 14 ].…”

Section: Decidualization: Morphological Differentiation In the Hummentioning

confidence: 99%

“…Several studies indicate that IL-15 plays various important roles in NK cell biology via binding these receptors [ 88 ]. Previous quantitative polymerase chain reaction (PCR) studies show that IL15 expression is significantly higher during the secretory phase in the human endometrium [ 10 , 25 ]. Histological analysis using human endometrial tissues also indicates that IL15 increases in the secretory phase [ 10 ] and is observed in many ESCs in the endometrium during this phase [ 10 ].…”

Section: Il-15mentioning

confidence: 99%

“…Previous quantitative polymerase chain reaction (PCR) studies show that IL15 expression is significantly higher during the secretory phase in the human endometrium [ 10 , 25 ]. Histological analysis using human endometrial tissues also indicates that IL15 increases in the secretory phase [ 10 ] and is observed in many ESCs in the endometrium during this phase [ 10 ]. Moreover, cultured human ESCs increase IL-15 secretion during the progestin-induced decidualization [ 89 ].…”

Section: Il-15mentioning

confidence: 99%

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Immune Tolerance of the Human Decidua

Murata

Tanaka

Okada

2021

JCM

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The endometrium is necessary for implantation, complete development of the placenta, and a successful pregnancy. The endometrium undergoes repeated cycles of proliferation, decidualization (differentiation), and shedding during each menstrual cycle. The endometrium—including stromal, epithelial, vascular endothelial, and immune cells—is both functionally and morphologically altered in response to progesterone, causing changes in the number and types of immune cells. Immune cells make up half of the total number of endometrial cells during implantation and menstruation. Surprisingly, immune tolerant cells in the endometrium (uterine natural killer cells, T cells, and macrophages) have two conflicting functions: to protect the body by eliminating pathogenic microorganisms and other pathogens and to foster immunological change to tolerate the embryo during pregnancy. One of the key molecules involved in this control is the cytokine interleukin-15 (IL-15), which is secreted by endometrial stromal cells. Recently, it has been reported that IL-15 is directly regulated by the transcription factor heart- and neural crest derivatives-expressed protein 2 in endometrial stromal cells. In this review, we outline the significance of the endometrium and immune cell population during menstruation and early pregnancy and describe the factors involved in immune tolerance and their involvement in the establishment and maintenance of pregnancy.

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The transcription factor HAND2 up-regulates transcription of the IL15 gene in human endometrial stromal cells

Cited by 40 publications

References 43 publications

Classification of gastric cancers based on immunogenomic profiling

Classification of gastric cancers based on immunogenomic profiling

Evolutionary transcriptomics implicatesHAND2in the origins of implantation and regulation of gestation length

Immune Tolerance of the Human Decidua

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