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

2020 ◽  
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.

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

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Mirna Marinić ◽  
Katelyn Mika ◽  
Sravanthi Chigurupati ◽  
Vincent J Lynch
Keyword(s):  
Preterm Birth ◽  
Menstrual Cycle ◽  
Cell Types ◽  
Estrogen Signaling ◽  
Gestation Length ◽  
Stromal Fibroblasts ◽  
Extravillous Cytotrophoblasts ◽  
Length Regulation ◽  
Blastocyst Implantation ◽  
Maternal Fetal Interface

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.

scholarly journals Cell type–specific actions of Bcl11b in early T-lineage and group 2 innate lymphoid cells

2019 ◽  
Vol 217 (1) ◽  
Author(s):  
Hiroyuki Hosokawa ◽  
Maile Romero-Wolf ◽  
Qi Yang ◽  
Yasutaka Motomura ◽  
Ditsa Levanon ◽  
...  
Keyword(s):  
T Cells ◽  
Target Genes ◽  
Cell Types ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Cell Type ◽  
Distal Enhancer ◽  
Distinct Cell Type ◽  
Cell Type Specific ◽  
Group 2

The zinc finger transcription factor, Bcl11b, is expressed in T cells and group 2 innate lymphoid cells (ILC2s) among hematopoietic cells. In early T-lineage cells, Bcl11b directly binds and represses the gene encoding the E protein antagonist, Id2, preventing pro-T cells from adopting innate-like fates. In contrast, ILC2s co-express both Bcl11b and Id2. To address this contradiction, we have directly compared Bcl11b action mechanisms in pro-T cells and ILC2s. We found that Bcl11b binding to regions across the genome shows distinct cell type–specific motif preferences. Bcl11b occupies functionally different sites in lineage-specific patterns and controls totally different sets of target genes in these cell types. In addition, Bcl11b bears cell type–specific post-translational modifications and organizes different cell type–specific protein complexes. However, both cell types use the same distal enhancer region to control timing of Bcl11b activation. Therefore, although pro-T cells and ILC2s both need Bcl11b for optimal development and function, Bcl11b works substantially differently in these two cell types.

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

2018 ◽  
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.

scholarly journals Transcriptome and regulatory maps of decidua-derived stromal cells inform gene discovery in preterm birth

2020 ◽  
Vol 6 (49) ◽  
pp. eabc8696
Author(s):  
Noboru J. Sakabe ◽  
Ivy Aneas ◽  
Nicholas Knoblauch ◽  
Debora R. Sobreira ◽  
Nicole Clark ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Stromal Cells ◽  
Target Genes ◽  
Association Studies ◽  
Cell Types ◽  
Chromatin Interaction ◽  
Open Chromatin ◽  
Genome Wide Association Studies ◽  
Functional Annotations ◽  
Gestational Duration

While a genetic component of preterm birth (PTB) has long been recognized and recently mapped by genome-wide association studies (GWASs), the molecular determinants underlying PTB remain elusive. This stems in part from an incomplete availability of functional genomic annotations in human cell types relevant to pregnancy and PTB. We generated transcriptome (RNA-seq), epigenome (ChIP-seq of H3K27ac, H3K4me1, and H3K4me3 histone modifications), open chromatin (ATAC-seq), and chromatin interaction (promoter capture Hi-C) annotations of cultured primary decidua-derived mesenchymal stromal/stem cells and in vitro differentiated decidual stromal cells and developed a computational framework to integrate these functional annotations with results from a GWAS of gestational duration in 56,384 women. Using these resources, we uncovered additional loci associated with gestational duration and target genes of associated loci. Our strategy illustrates how functional annotations in pregnancy-relevant cell types aid in the experimental follow-up of GWAS for PTB and, likely, other pregnancy-related conditions.

scholarly journals Transcriptome and regulatory maps of decidua-derived stromal cells inform gene discovery in preterm birth

2020 ◽  
Author(s):  
Noboru Sakabe ◽  
Ivy Aneas ◽  
Nicholas Knoblauch ◽  
Debora R. Sobreira ◽  
Nicole Clark ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Stromal Cells ◽  
Target Genes ◽  
Association Studies ◽  
Cell Types ◽  
Genome Wide Association Studies ◽  
Functional Annotations ◽  
Significant Enrichment ◽  
Gestational Duration

AbstractWhile a genetic component of preterm birth (PTB) has long been recognized and recently mapped by genome-wide association studies (GWAS), the molecular determinants underlying PTB remain elusive. This stems in part from an incomplete availability of comprehensive functional genomic annotations in human cell types relevant to pregnancy and PTB. Here, we generated extensive transcriptional and chromatin annotations of cultured primary decidua-derived mesenchymal stromal/stem cells (MSCs) and in vitro differentiated decidual stromal cells (DSCs) and developed a computational framework to integrate these functional annotations with results from a GWAS of gestational duration in 56,384 women. This resulted in a significant enrichment of heritability estimates in functional noncoding regions in stromal cells, as well as in the discovery of additional loci associated with gestational duration and target genes of associated loci. Our strategy illustrates how systematic functional annotations in pregnancy-relevant cell types aid in the experimental follow-up of GWAS for PTB and, likely, other pregnancy-related conditions.

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

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.

scholarly journals Annotation of chromatin states in 66 complete mouse epigenomes during development

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Arjan van der Velde ◽  
Kaili Fan ◽  
Junko Tsuji ◽  
Jill E. Moore ◽  
Michael J. Purcaro ◽  
...  
Keyword(s):  
Target Genes ◽  
Cell Types ◽  
Developmental Trajectory ◽  
Phase Iii ◽  
Chromatin State ◽  
Mammalian Development ◽  
Chromatin States ◽  
Transcription Start Sites ◽  
Repressive Mark ◽  
Distinct Cell

AbstractThe morphologically and functionally distinct cell types of a multicellular organism are maintained by their unique epigenomes and gene expression programs. Phase III of the ENCODE Project profiled 66 mouse epigenomes across twelve tissues at daily intervals from embryonic day 11.5 to birth. Applying the ChromHMM algorithm to these epigenomes, we annotated eighteen chromatin states with characteristics of promoters, enhancers, transcribed regions, repressed regions, and quiescent regions. Our integrative analyses delineate the tissue specificity and developmental trajectory of the loci in these chromatin states. Approximately 0.3% of each epigenome is assigned to a bivalent chromatin state, which harbors both active marks and the repressive mark H3K27me3. Highly evolutionarily conserved, these loci are enriched in silencers bound by polycomb repressive complex proteins, and the transcription start sites of their silenced target genes. This collection of chromatin state assignments provides a useful resource for studying mammalian development.

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

2008 ◽  
Vol 28 (24) ◽  
pp. 7487-7503 ◽  
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.

scholarly journals Thyroid Hormone Action in Cerebellum and Cerebral Cortex Development

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Fabrice Chatonnet ◽  
Frédéric Picou ◽  
Teddy Fauquier ◽  
Frédéric Flamant
Keyword(s):  
Cerebral Cortex ◽  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Glial Cell ◽  
Nuclear Receptors ◽  
Target Genes ◽  
Cell Types ◽  
Hormone Action ◽  
Cerebral Cortex Development ◽  
Thyroid Hormone Action

Thyroid hormones (TH, including the prohormone thyroxine (T4) and its active deiodinated derivative 3,,5-triiodo-L-thyronine (T3)) are important regulators of vertebrates neurodevelopment. Specific transporters and deiodinases are required to ensure T3 access to the developing brain. T3 activates a number of differentiation processes in neuronal and glial cell types by binding to nuclear receptors, acting directly on transcription. Only few T3 target genes are currently known. Deeper investigations are urgently needed, considering that some chemicals present in food are believed to interfere with T3 signaling with putative neurotoxic consequences.

scholarly journals ACE2: the molecular doorway to SARS-CoV-2

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Miriam Marlene Medina-Enríquez ◽  
Sandra Lopez-León ◽  
José Alberto Carlos-Escalante ◽  
Zuleika Aponte-Torres ◽  
Angelica Cuapio ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Cell Types ◽  
Negative Regulator ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Functional Activities ◽  
Pathological Conditions ◽  
Organ Systems ◽  
Different Cell Types ◽  
Functional Receptor

AbstractThe angiotensin-converting enzyme 2 (ACE2) is the host functional receptor for the new virus SARS-CoV-2 causing Coronavirus Disease 2019. ACE2 is expressed in 72 different cell types. Some factors that can affect the expression of the ACE2 are: sex, environment, comorbidities, medications (e.g. anti-hypertensives) and its interaction with other genes of the renin-angiotensin system and other pathways. Different factors can affect the risk of infection of SARS-CoV-2 and determine the severity of the symptoms. The ACE2 enzyme is a negative regulator of RAS expressed in various organ systems. It is with immunity, inflammation, increased coagulopathy, and cardiovascular disease. In this review, we describe the genetic and molecular functions of the ACE2 receptor and its relation with the physiological and pathological conditions to better understand how this receptor is involved in the pathogenesis of COVID-19. In addition, it reviews the different comorbidities that interact with SARS-CoV-2 in which also ACE2 plays an important role. It also describes the different factors that interact with the virus that have an influence in the expression and functional activities of the receptor. The goal is to provide the reader with an understanding of the complexity and importance of this receptor.

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