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Simak Ali, Kirsty Balachandran and Bert W O'Malley
Leonard Ym Cheung and Karine Rizzoti
In the last 15 years, single-cell technologies have become robust and indispensable tools to investigate cell heterogeneity. Beyond transcriptomic, genomic and epigenome analyses, technologies are constantly evolving, in particular toward multi-omics, where analyses of different source materials from a single cell are combined, and spatial transcriptomics where resolution of cellular heterogeneity can be detected in situ. While some of these techniques are still being optimised, single-cell RNAseq has commonly been used because the examination of transcriptomes allows characterization of cell identity, and therefore unravel previously uncharacterised diversity within cell populations. Most endocrine organs have now been investigated using this technique, and this has given new insights into organ embryonic development, characterization of rare cell types, and disease mechanisms. Here we highlight recent studies, particularly on the hypothalamus and pituitary, and examine recent findings on the pancreas and reproductive organs where many single-cell experiments have been performed.
Miguel Beato, Roni H. G. Wright and François Le Dily
Gene regulation by steroid hormones has been at the forefront in elucidating the intricacies of transcriptional regulation in eukaryotes ever since the discovery by Karlson and Clever that the insect steroid hormone ecdysone induces chromatin puffs in giant chromosomes. After the successful cloning of the hormone receptors towards the end of the past century, detailed mechanistic insight emerged in some model systems, in particular the MMTV provirus. With the arrival of next generation DNA sequencing and the omics techniques we have gained even further insight into the global cellular response to steroid hormones that in the past decades also extended to the function of the 3D genome topology. More recently advances in high resolution microcopy, single cell genomics and the new vision of liquid-liquid phase transitions in the context of nuclear space brings us closer than ever to unravelling the logic of gene regulation and its complex integration of global cellular signaling networks. Using the function of progesterone and its cellular receptor in breast cancer cells we will briefly summarize the history and describe the present extent of our knowledge on how regulatory proteins deal with the chromatin structure to gain access to DNA sequences and interpret the genomic instructions that enable cells to respond selectively to external signals by reshaping their gene regulatory networks.
Rebecca Roy, Caitlyn Nguyen-Ngo and Martha Lappas
Gestational diabetes mellitus (GDM) affects up to 16% of pregnant women and is associated with significant long-term health detriments for mum and her offspring. Two central features of GDM are low-grade inflammation and maternal peripheral insulin resistance, therefore therapeutics which target these may be most effective at preventing the development of GDM. Short-chain fatty acids (SCFAs), such as butyrate and propionate, are metabolites produced from the fermentation of dietary fibre by intestinal microbiota. SCFAs possess anti-inflammatory, anti-obesity and anti-diabetic properties. Therefore, this study aimed to investigate the effect of SCFAs on inflammation and insulin signalling defects in an in vitro model of GDM. Human placenta, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were stimulated with either the pro-inflammatory cytokine TNF or bacterial product lipopolysaccharide (LPS). The SCFAs butyrate and propionate blocked TNF- and LPS-induced mRNA expression and secretion of pro-inflammatory cytokines and chemokines in placenta, VAT and SAT. Primary human cells isolated from skeletal muscle were stimulated with TNF to assess the effect of SCFAs on inflammation-induced defects in the insulin signalling pathway. Butyrate and propionate were found to reverse TNF-induced increases in IRS-1 serine phosphorylation and decreases in glucose uptake. Butyrate and propionate exerted these effects by preventing ERK activation. Taken together, these results suggest that the SCFAs may be able to improve insulin sensitivity and prevent inflammation induced by sterile or bacterial inflammation. Future in vivo studies are warranted to investigate the efficacy and safety of SCFAs in preventing insulin resistance and inflammation associated with GDM.
Hong Zhu, Wei Cao, Peng Zhao, Jieyu Wang, Yuying Qian and Yun Li
The excessive activation of renin-angiotensin system (RAS) is one of key pathophysiological characteristics in the development of cardiac remodelling. Angiotensin (Ang) II, as a main active peptide in RAS, induces cardiac structural disorders and dysfunction. However, the molecular mechanisms are still not fully disclosed. Present study aimed to determine the role and potential mechanisms of cardiac TIR-domain-containing adapter-inducing interferon-β (TRIF) in Ang II-mediated cardiac remodelling in mice. In vitro and in vivo studies showed Ang II obviously increased the expression of TRIF, accompanied with cardiac structural abnormalities and functional injuries. Specific blockage of cardiac TRIF effectively decreased Ang II-induced cardiac inflammation, fibrosis, hypertrophy and dysfunction in mice. Mechanistically, the TRIF triggered the activation of epidermal growth factor receptor (EGFR) signalling by nuclear factor (NF)-κB transcriptional regulation and downstream EGFR ligands. Taken together, present study supported cardiac TRIF was a potential therapeutic target for attenuating cardiac pathophysiological remodelling. The TRIF/EGFR axis partially explained the molecular mechanism of Ang II-induced cardiac inflammation, fibrosis, hypertrophy and dysfunction in mice.
Lekha Jain, Tayaza Fadason, William Schierding, Mark H Vickers, Justin M O’Sullivan and Jo K Perry
Growth hormone (GH) is a peptide hormone predominantly produced by the anterior pituitary and is essential for normal growth and metabolism. The GH locus contains five evolutionarily related genes under the control of an upstream locus control region that coordinates tissue-specific expression of these genes. Compromised GH signalling and genetic variation in these genes has been implicated in various disorders including cancer. We hypothesised that regulatory regions within the GH locus coordinate expression of a gene network that extends the impact of the GH locus control region. We used the CoDeS3D algorithm to analyse 529 common single nucleotide polymorphisms (SNPs) across the GH locus. This algorithm identifies colocalised Hi-C and eQTL associations to determine which SNPs are associated with a change in gene expression at loci that physically interact within the nucleus. One hundred and eighty-one common SNPs were identified that interacted with 292 eGenes across 48 different tissues. One hundred and forty-five eGenes were regulated in trans. eGenes were found to be enriched in GH/GHR-related cellular signalling pathways including MAPK, PI3K-AKT-mTOR, ERBB and insulin signalling, suggesting that these pathways may be co-regulated with GH signalling. Enrichment was also observed in the Wnt and Hippo signalling pathways and in pathways associated with hepatocellular, colorectal, breast and non-small cell lung carcinoma. Thirty-three eQTL SNPs identified in our study were found to be of regulatory importance in a genome-wide Survey of Regulatory Elements reporter screen. Our data suggest that the GH locus functions as a complex regulatory region that coordinates expression of numerous genes in cis and trans, many of which may be involved in modulating GH function in normal and disease states.
Maya Elena Lee, Aisha Aderayo Tepede, Adel Mandl, Lee Scott Weinstein, Jaydira del Rivero, Sunita K Agarwal and Jenny E. Blau
Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) comprise a heterogenous and diverse group of neoplasms arising from a common neuroendocrine cell origin. The majority of these tumors occur sporadically while ~20% manifest within the context of hereditary syndromes. Germline MEN1 mutations cause a syndrome with an increased susceptibility to multifocal primary GEP NETs. In addition, MEN1 mutations also occur in sporadic GEP NETs. MEN1 alternations are the most frequent sporadic mutation found in pancreatic neuroendocrine tumors (PNETs). We explore the implication of the loss of the MEN1 encoded protein menin as a key pathogenic driver in subsets of GEP NETs with downstream consequences including upregulation of the oncogenic receptor c-MET (hepatocyte growth factor receptor). This review will summarize the data related to the clinical presentation, therapeutic standards, and outcomes of sporadic and MEN1 associated GEP NETs. We present the data on c-MET expression in GEP NETs, clinical trials using c-MET inhibtors, and provide an overview of the molecular mechanisms by which c-MET inhibition in GEP NETs represents a potential precision-medicine targeted approach.
Andrea Hanel, Henna-Riikka Malmberg and Carsten Carlberg
Molecular endocrinology of vitamin D is based on the activation of the transcription factor vitamin D receptor (VDR) by the vitamin D metabolite 1α,25-dihydroxyvitamin D3. This nuclear vitamin D-sensing process causes epigenome-wide effects, such as changes in chromatin accessibility as well as in the contact of VDR and its supporting pioneer factors with thousands of genomic binding sites, referred to as vitamin D response elements. VDR binding enhancer regions loop to transcription start sites of hundreds of vitamin D target genes resulting in changes of their expression. Thus, vitamin D signaling is based on epigenome- and transcriptome-wide shifts in VDR-expressing tissues. Monocytes are the most responsive cell type of the immune system and serve as a paradigm for uncovering the chromatin model of vitamin D signaling. In this review, an alternative approach for selecting vitamin D target genes is presented, which are most relevant for understanding the impact of vitamin D endocrinology on innate immunity. Different scenarios of the regulation of primary upregulated vitamin D target genes are presented, in which vitamin D-driven super-enhancers comprise a cluster of persistent (constant) and/or inducible (transient) VDR-binding sites. In conclusion, the spatio-temporal VDR binding in the context of chromatin is most critical for the regulation of vitamin D target genes.
Yawen Xu, Jinhua Lu, Jinxiang Wu, Ruiwei Jiang, Chuanhui Guo, Yedong Tang, Haibin Wang, Shuangbo Kong and Suqing Wang
Decidualization is a critical process for embryo implantation and pregnancy maintenance in humans. The homeobox gene HOXA10 has been widely studied in endometrial receptivity establishment and decidualization. MEIS1, a three-amino-acid loop extension (TALE) family homeobox gene, has been proven to be a co-factor for HOXA10 in mouse uterus. However, the interaction between MEIS1 and HOXA10 in the human decidual cells remains to be elucidated. siRNA and CRISPR-Cas9 were employed to knockdown and knockout MEIS1 in the cultured human endometrial stromal cells, and it was found that MEIS1 deficiency leads to impaired decidualization. The physical interaction between the MEIS1 and HOXA10 in human endometrial stromal cell was confirmed by immunoprecipitation. Moreover, KAT2B and ETA were proved to be downregulated in the absence of MEIS1, and luciferase reporter and ChIP assays demonstrated that MEIS1-HOXA10 complex binds to the promoters of KAT2B and ETA and regulates their activity. Overexpression of KAT2B and ETA can partially rescue the decidualization defects in MEIS1-knockout HESCs. Taken together, these data suggest that MEIS1 plays an indispensable role in decidualization in human endometrial stromal cells, and MEIS1 interacts with HOXA10 to regulate the downstream genes, such as KAT2B and ETA. These findings will contribute to our understanding about the regulatory network in the process of decidualization in humans.
Jingyi Luo, Tingting Liu and Weiping Teng
Hashimoto’s thyroiditis (HT) is a common organ-specific autoimmune disease, which develops in 0.3–1.5/1000 subjects annually. The aims of this study were to determine the lncRNA profile in peripheral blood CD4+ T cells from HT patients and then to characterize the potential function of NONHSAT079547.2. A total of 37 HT patients and 50 sex- and age-matched healthy controls were enrolled for high-throughput sequencing. Another 43 HT patients and 50 sex- and age-matched controls were enrolled for validation via real-time PCR. Flow cytometry and CCK8 assays were used to measure cell apoptosis and growth levels. Western blotting was used for measuring the expression of growth- and apoptosis-associated proteins. IL-17 serum concentration and transcriptional level in CD4+ T cells of participants were detected by ELISA and real-time PCR, respectively. The mechanism of competitive endogenous RNA was determined using real-time PCR, ELISA, RNA immunoprecipitation, and dual-luciferase assays in Jurkat cells. A total of 7564 significantly differentially expressed lncRNAs were found, of which 3913 lncRNAs were upregulated and 3651 lncRNAs were downregulated in HT group when compared to control group. NONHSAT079547.2 was significantly upregulated in HT patients and was positively correlated with serum thyroid peroxidase antibody level. Further studies confirmed that NONHSAT079547.2 could promote cell growth and control IL-17 expression and secretion via the NONHSAT079547.2/miR-4716-5p/IL-17 axis.This is the first study to describe the lncRNA profile in CD4+ T cells of HT patients. The studies on the function of NONHSAT079547.2 might elucidate the underlying molecular mechanisms and represent potential biomarkers for HT.