Evolutionary transcriptomics implicates HAND2 in the origins of implantation and regulation of gestation length

The developmental origins and evolutionary histories of cell types, tissues, and organs contribute to the ways in which their dysfunction produces disease. In mammals, the nature, development and evolution of maternal-fetal interactions likely influence diseases of pregnancy. Here we show genes that evolved expression at the maternal-fetal interface in Eutherian mammals play essential roles in the evolution of pregnancy and are associated with immunological disorders and preterm birth. Among these genes is HAND2, a transcription factor that suppresses estrogen signaling, a Eutherian innovation allowing blastocyst implantation. We found dynamic HAND2 expression in the decidua throughout the menstrual cycle and pregnancy, gradually decreasing to a low at term. HAND2 regulates a distinct set of genes in endometrial stromal fibroblasts including IL15, a cytokine also exhibiting dynamic expression throughout the menstrual cycle and gestation, promoting migration of natural killer cells and extravillous cytotrophoblasts. We demonstrate that HAND2 promoter loops to an enhancer containing SNPs implicated in birth weight and gestation length regulation. Collectively, these data connect HAND2 expression at the maternal-fetal interface with evolution of implantation and gestational regulation, and preterm birth.

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Evolutionary transcriptomics implicates HAND2 in the origins of implantation and regulation of gestation length

10.1101/2020.06.15.152868 ◽

2020 ◽

Cited By ~ 1

Author(s):

Mirna Marinić ◽

Katelyn Mika ◽

Sravanthi Chigurupati ◽

Vincent J. Lynch

Keyword(s):

Preterm Birth ◽

Menstrual Cycle ◽

Target Genes ◽

Cell Types ◽

Estrogen Signaling ◽

Gestation Length ◽

Distal Enhancer ◽

Stromal Fibroblasts ◽

Organ Systems ◽

Maternal Fetal Interface

AbstractThe 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, an innovation of Eutherians, thereby allowing blastocyst implantation. 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 connect HAND2 expression at the maternal-fetal interface with the evolution of implantation and gestation length regulation, and preterm birth.

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Single cell RNAseq provides a molecular and cellular cartography of changes to the human endometrium through the menstrual cycle

10.1101/350538 ◽

2018 ◽

Cited By ~ 5

Author(s):

Wanxin Wang ◽

Felipe Vilella ◽

Pilar Alama ◽

Inmaculada Moreno ◽

Marco Mignardi ◽

...

Keyword(s):

Menstrual Cycle ◽

Single Cell ◽

Cell Types ◽

Human Endometrium ◽

Cellular Heterogeneity ◽

Cell Type ◽

Stromal Fibroblasts ◽

Unique Type ◽

Ciliated Epithelial Cell ◽

Human Menstrual Cycle

SummaryIn a human menstrual cycle, the endometrium undergoes remodeling, shedding, and regeneration, all of which are driven by substantial gene expression changes in the underlying cellular hierarchy. Despite its importance in human fertility and regenerative biology, mechanistic understanding of this unique type of tissue homeostasis remains rudimentary. We characterized the transcriptomic transformation of human endometrium at single cell resolution, dissecting the multidimensional cellular heterogeneity of this tissue across the entire natural menstrual cycle. We profiled the behavior of 6 endometrial cell types, including a previously uncharacterized ciliated epithelial cell type, during four major phases of endometrial transformation, and found characteristic signatures for each cell type and phase. We discovered that human window of implantation opens with an abrupt and discontinuous transcriptomic activation in the epithelia, accompanied with widespread decidualized feature in the stromal fibroblasts. These data reveal signatures in the luminal and glandular epithelia during epithelial gland reconstruction, and suggest a mechanism for adult gland formation.

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Morphological features of endo- and myometrium in patients with uterine leiomyoma and infertility

HEALTH OF WOMAN ◽

10.15574/hw.2020.151-152.33 ◽

2020 ◽

pp. 33-37

Author(s):

M.A. Flaksenberg ◽

◽

Keyword(s):

Uterine Leiomyoma ◽

Negative Impact ◽

Reproductive Function ◽

Cell Types ◽

Underlying Disease ◽

Reproductive Organs ◽

Pathological Process ◽

Simple Type ◽

Morphological Examination ◽

Blastocyst Implantation

The objective: determination of morphofunctional features of leiomatous nodes and endometrium in women with uterine leiomyoma and infertility to restore reproductive function and prevent recurrence of the underlying disease. Materials and methods. In order to restore reproductive function and prevent recurrence of the underlying disease, morphofunctional features of leiomatous nodes and endometrium in women with uterine leiomyoma and infertility were determined. Thirty samples of leiomyomatous nodes and endometrium were examined, among which 15 were obtained from women with multiple uterine leiomyoma and infertility and 15 samples from women with uterine leiomyoma with isolated uterine leiomyoma. During the study, a general-histological method was used for staining with hematoxylin-eosin and picrofuxin by van Gizon, as well as immunohistochemical methods. Histological examination of the endometrium was performed according to conventional protocol, taking into account the day of the menstrual cycle and R.W. Noyes criteria. Results. In the morphological examination of leiomyomatous nodes in the vast majority of cases the presence of uterine leiomyomas of simple and cell types or their combination was established. In women with multiple uterine leiomyoma, simple-type leiomyoma (53.3%) was predominant, and in patients with isolated leiomyoma the signs of cellular uterine leiomyoma (66.7%) were more frequently found. In 80.0% of women with uterine leiomyoma revealed pathology of the endometrium, such as glandular and glandular-fibrous polyps, simple and complex atypical endometrial hyperplasia, which confirms the theory about the only pathogenetic mechanisms of the emergence of hyperplastic processes of female organs. In 66.7% of women with multiple leiomyomas, signs of chronic endometritis have been found, which exacerbates the pathological process and can have a negative impact on the reproductive function, such as secretory endometrial transformation and impaired blastocyst implantation, and explains a much higher percentage of infertility in the group. Conclusion. In women with impaired reproductive function, patients with uterine leiomyoma, it is necessary to conduct a study of the receptivity of the reproductive organs, namely - the endometrium and leiomatous nodes. This will make it possible to use one or another method of treatment in order to restore reproductive function and prevent recurrence of the underlying disease. Keywords: infertility, uterine leiomyoma, endometrium, receptive apparatus.

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Single cell transcriptomic analysis of murine lung development on hyperoxia-induced damage

Nature Communications ◽

10.1038/s41467-021-21865-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Maria Hurskainen ◽

Ivana Mižíková ◽

David P. Cook ◽

Noora Andersson ◽

Chanèle Cyr-Depauw ◽

...

Keyword(s):

Single Cell ◽

Lung Development ◽

Alveolar Epithelium ◽

Cell Types ◽

Capillary Endothelium ◽

Stromal Fibroblasts ◽

Main Driver ◽

Macrophage Populations ◽

Induced Changes ◽

Cellular Compartments

AbstractDuring late lung development, alveolar and microvascular development is finalized to enable sufficient gas exchange. Impaired late lung development manifests as bronchopulmonary dysplasia (BPD) in preterm infants. Single-cell RNA sequencing (scRNA-seq) allows for assessment of complex cellular dynamics during biological processes, such as development. Here, we use MULTI-seq to generate scRNA-seq profiles of over 66,000 cells from 36 mice during normal or impaired lung development secondary to hyperoxia with validation of some of the findings in lungs from BPD patients. We observe dynamic populations of cells, including several rare cell types and putative progenitors. Hyperoxia exposure, which mimics the BPD phenotype, alters the composition of all cellular compartments, particularly alveolar epithelium, stromal fibroblasts, capillary endothelium and macrophage populations. Pathway analysis and predicted dynamic cellular crosstalk suggest inflammatory signaling as the main driver of hyperoxia-induced changes. Our data provides a single-cell view of cellular changes associated with late lung development in health and disease.

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AKT Alters Genome-Wide Estrogen Receptor α Binding and Impacts Estrogen Signaling in Breast Cancer

Molecular and Cellular Biology ◽

10.1128/mcb.00799-08 ◽

2008 ◽

Vol 28 (24) ◽

pp. 7487-7503 ◽

Cited By ~ 72

Author(s):

Poornima Bhat-Nakshatri ◽

Guohua Wang ◽

Hitesh Appaiah ◽

Nikhil Luktuke ◽

Jason S. Carroll ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Binding Sites ◽

Transforming Growth Factor ◽

Cell Types ◽

Estrogen Receptor Α ◽

Estrogen Signaling ◽

Primary Tumors ◽

Genome Wide ◽

Extracellular Signal

ABSTRACT Estrogen regulates several biological processes through estrogen receptor α (ERα) and ERβ. ERα-estrogen signaling is additionally controlled by extracellular signal activated kinases such as AKT. In this study, we analyzed the effect of AKT on genome-wide ERα binding in MCF-7 breast cancer cells. Parental and AKT-overexpressing cells displayed 4,349 and 4,359 ERα binding sites, respectively, with ∼60% overlap. In both cell types, ∼40% of estrogen-regulated genes associate with ERα binding sites; a similar percentage of estrogen-regulated genes are differentially expressed in two cell types. Based on pathway analysis, these differentially estrogen-regulated genes are linked to transforming growth factor β (TGF-β), NF-κB, and E2F pathways. Consistent with this, the two cell types responded differently to TGF-β treatment: parental cells, but not AKT-overexpressing cells, required estrogen to overcome growth inhibition. Combining the ERα DNA-binding pattern with gene expression data from primary tumors revealed specific effects of AKT on ERα binding and estrogen-regulated expression of genes that define prognostic subgroups and tamoxifen sensitivity of ERα-positive breast cancer. These results suggest a unique role of AKT in modulating estrogen signaling in ERα-positive breast cancers and highlights how extracellular signal activated kinases can change the landscape of transcription factor binding to the genome.

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Human vulnerability to cancer malignancy is enhanced by evolution of higher mesenchymal CD44 expression compared to other mammals

10.1101/2020.08.03.234617 ◽

2020 ◽

Cited By ~ 1

Author(s):

Xinghong Ma ◽

Anasuya Dighe ◽

Jamie Maziarz ◽

Edwin Neumann ◽

Eric Erkenbrack ◽

...

Keyword(s):

Cancer Progression ◽

Bos Taurus ◽

Cell Types ◽

Skin Fibroblasts ◽

Proximal Promoter ◽

Promoting Effect ◽

Stromal Fibroblasts ◽

Human Vulnerability ◽

Cd44 Expression ◽

Regulatory Effects

AbstractCD44 is a membrane-bound extracellular matrix (ECM) receptor interacting, among others, with hyaluronic acid (HA) and osteopontin (OPN). Cancer progression and metastasis are greatly influenced by the cancer micro-environment, consisting of ECM, immune cells and cancer-associated fibroblasts (CAF). Recruitment of fibroblasts (FB) into the role as CAFs is caused by paracrine signals from the tumor, including TGFb1, PDGF and OPN. The effect of OPN on the transformation of FB into CAF is mediated by CD44. CD44 expression in human skin and endometrial stromal fibroblasts (SF and ESF, respectively) also enhances invasibility of stroma by trophoblast as well as cancer cells. Here we study the evolution of CD44 expression in therian mammals in both SF as well as ESF and demonstrate that the human lineage has experienced a concerted evolutionary enhancement of CD44 expression in SF and ESF, correlating with an increase in human vulnerability to cancer malignancy. In both human and cattle (Bos taurus), the dominant isoforms are CD44s and CD44v10 with 9 and 10 exons, respectively. CD44s is an isoform strongly associated with malignancy. In humans, an additional isoform is expressed: HsaCD44-205 with 8 exons not found in cattle. We show that the concerted increase of CD44 expression in SF and ESF is largely due to cis-regulatory effects in the proximal promoter of CD44. We identify a primate specific acquisition of CEBPB binding sites in the CD44 promoter. Recruitment of CEBPB into CD44 regulation explains almost 50% of the lineage-specific increased CD44 expression in primate skin fibroblasts but is not necessary for high CD44 expression in ESF. All these results suggest that selective modulation of CD44 expression in skin fibroblasts could attenuate the cancer-promoting effect of CAF recruitment in the skin with minimal side effects on other cell types. Additional experimental data is needed to explore this possibility.

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Relevant Cytokines in the B Cell Lymphoma Micro-Environment

Cancers ◽

10.3390/cancers12092525 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2525

Author(s):

Günter Krause ◽

Floyd Hassenrück ◽

Michael Hallek

Keyword(s):

B Cell ◽

Cytokine Production ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Cell Types ◽

Cell Receptor ◽

Lymphocytic Leukemia ◽

Blood Levels ◽

Stromal Fibroblasts

Cytokines are soluble protein factors with importance in intercellular communication and, as such, play pivotal roles in the pathogenesis of B cell malignancies. Evidence from in vitro cultures permitted us to choose example cytokines that bind to different biochemical receptor types. Activated malignant B cells or stromal fibroblasts and macrophages prominently secrete the chemokines CCL3 or CXCL12 and CXCL13, respectively. Apart from helper T cells, various cell types of the B cell lymphoma microenvironment are capable of producing the cytokines IL-4, IL-6, IL-10 and TNFα. Owing to its impact on the development of myeloid cells, CSF-1 is among important soluble factors in the B cell lymphoma microenvironment. Inhibitors of B cell receptor-associated kinases often act via the blockade of cytokine production, but also prevent cytokine effects, e.g., chemotaxis. Increments in blood levels in chronic lymphocytic leukemia patients compared to healthy donors and normalization upon treatment with ibrutinib can be explained by producing cell types and modulation of cytokine production observed in vitro.

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Immunomodulatory Properties of HLA-G in Infectious Diseases

Journal of Immunology Research ◽

10.1155/2014/298569 ◽

2014 ◽

Vol 2014 ◽

pp. 1-14 ◽

Cited By ~ 36

Author(s):

Laurence Amiot ◽

Nicolas Vu ◽

Michel Samson

Keyword(s):

Infectious Diseases ◽

Complex Molecule ◽

Major Histocompatibility Complex Molecule ◽

Cell Types ◽

Inhibitory Effect ◽

New Therapeutic Approaches ◽

Extravillous Cytotrophoblasts ◽

Cellular Source ◽

Therapeutic Tools

HLA-G is a nonclassical major histocompatibility complex molecule first described at the maternal-fetal interface, on extravillous cytotrophoblasts. Its expression is restricted to some tissues in normal conditions but increases strongly in pathological conditions. The expression of this molecule has been studied in detail in cancers and is now also beginning to be described in infectious diseases. The relevance of studies on HLA-G expression lies in the well known inhibitory effect of this molecule on all cell types involved in innate and adaptive immunity, favoring escape from immune control. In this review, we summarize the features of HLA-G expression by type of infections (i.e, bacterial, viral, or parasitic) detailing the state of knowledge for each pathogenic agent. The polymorphism, the interference of viral proteins with HLA-G intracellular trafficking, and various cytokines have been described to modulate HLA-G expression during infections. We also discuss the cellular source of HLA-G, according to the type of infection and the potential role of HLA-G. New therapeutic approaches based on synthetic HLA-G-derived proteins or antibodies are emerging in mouse models of cancer or transplantation, and these new therapeutic tools may eventually prove useful for the treatment of infectious diseases.

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Infection of Placental Extravillous Cytotrophoblasts with Human Cytomegalovirus Causes a Treg/Th17 Imbalance at the Maternal–Fetal Interface

Cell Transplantation ◽

10.1177/0963689720925055 ◽

2020 ◽

Vol 29 ◽

pp. 096368972092505

Author(s):

Yuan Qiao ◽

Helena Kolibaba ◽

Yukiko Mori ◽

Tao Liu ◽

Huijun Chen ◽

...

Keyword(s):

Human Cytomegalovirus ◽

Th17 Cells ◽

Hcmv Infection ◽

First Trimester ◽

Treg Cells ◽

Control Group ◽

Messenger Ribonucleic Acid ◽

Extravillous Cytotrophoblasts ◽

Maternal Fetal Interface

This paper aimed to evaluate whether human cytomegalovirus (HCMV) infection in extravillous cytotrophoblasts (EVT) could shift the balance between regulatory T (Treg) and T-helper type 17 (Th17) cells in vitro. In this study, primary EVT isolated from first trimester placental tissues were infected with HCMV, and conditional media were harvested after cultivation for 72 h. T lymphocytes were cultured in the presence or absence of HCMV-infected conditional media. The frequencies of Th17 or Treg cells from HCMV group were significantly lower or higher than those from the control group, with the expression of corresponding key cytokines at both messenger ribonucleic acid and secretion levels, respectively. The ratio of Treg to Th17 cells was significantly lower in HCMV group than that in control group ( P < 0.01). In conclusion, tiled Th17/Treg balance at maternal–fetal interface exists after HCMV infection.

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Role of POT1 in Human Cancer

Cancers ◽

10.3390/cancers12102739 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2739 ◽

Cited By ~ 2

Author(s):

Yangxiu Wu ◽

Rebecca C. Poulos ◽

Roger R. Reddel

Keyword(s):

Human Cancer ◽

Cell Types ◽

Cancer Therapies ◽

Telomeric Dna ◽

Targeted Cancer Therapies ◽

Length Regulation ◽

Tumor Types ◽

Different Cell Types ◽

Essential Subunit

Telomere abnormalities facilitate cancer development by contributing to genomic instability and cellular immortalization. The Protection of Telomeres 1 (POT1) protein is an essential subunit of the shelterin telomere binding complex. It directly binds to single-stranded telomeric DNA, protecting chromosomal ends from an inappropriate DNA damage response, and plays a role in telomere length regulation. Alterations of POT1 have been detected in a range of cancers. Here, we review the biological functions of POT1, the prevalence of POT1 germline and somatic mutations across cancer predisposition syndromes and tumor types, and the dysregulation of POT1 expression in cancers. We propose a framework for understanding how POT1 abnormalities may contribute to oncogenesis in different cell types. Finally, we summarize the clinical implications of POT1 alterations in the germline and in cancer, and possible approaches for the development of targeted cancer therapies.

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