Sustained Intrinsic WNT and BMP4 Activation Impairs Hesc Diferentiation to Defnitive Endoderm and Drives the Cells Towards Extra‑Embryonic Mesoderm C
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Spontaneous Puberty in 46,XX Subjects with Congenital Lipoid Adrenal Hyperplasia
Spontaneous puberty in 46,XX subjects with congenital lipoid adrenal hyperplasia. Ovarian steroidogenesis is spared to some extent despite inactivating mutations in the steroidogenic acute regulatory protein (StAR) gene. K Fujieda, … , T Sugawara, J F Strauss 3rd J Clin Invest. 1997;99(6):1265-1271. https://doi.org/10.1172/JCI119284. Research Article Congenital lipoid adrenal hyperplasia (lipoid CAH) is the most severe form of CAH in which the synthesis of all gonadal and adrenal cortical steroids is markedly impaired. We report here the clinical, endocrinological, and molecular analyses of two unrelated Japanese kindreds of 46,XX subjects affected with lipoid CAH who manifested spontaneous puberty. Phenotypic female infants with 46,XX karyotypes were diagnosed with lipoid CAH as newborns based on a clinical history of failure to thrive, hyperpigmentation, hyponatremia, hyperkalemia, and low basal values of serum cortisol and urinary 17-hydroxycorticosteroid and 17-ketosteroid. These patients responded to treatment with glucocorticoid and 9alpha- fludrocortisone. Spontaneous thelarche occurred in association with increased serum estradiol levels at the age of 10 and 11 yr, respectively. Pubic hair developed at the age of 12 yr 11 mo in one subject and menarche was at the age of 12 yr in both cases. Both subjects reported periodic menstrual bleeding and subsequently developed polycystic ovaries. To investigate the molecular basis of the steroidogenic lesion in these patients, the StAR gene was characterized by PCR and direct DNA sequence -
Biochemical Mechanisms of Thyroid Hormone Deiodination
THYROID Volume 15, Number 8, 2005 © Mary Ann Liebert, Inc. Biochemical Mechanisms of Thyroid Hormone Deiodination George G.J.M. Kuiper, Monique H.A. Kester, Robin P. Peeters, and Theo J. Visser Deiodination is the foremost pathway of thyroid hormone metabolism not only in quantitative terms but also because thyroxine (T4) is activated by outer ring deiodination (ORD) to 3,3’,5-triiodothyronine (T3), whereas both T4 and T3 are inactivated by inner ring deiodination (IRD) to 3,3’,5-triiodothyronine and 3,3’- diiodothyronine, respectively. These reactions are catalyzed by three iodothyronine deiodinases, D1-3. Although they are homologous selenoproteins, they differ in important respects such as catalysis of ORD and/or IRD, deiodination of sulfated iodothyronines, inhibition by the thyrostatic drug propylthiouracil, and regulation during fetal and neonatal development, by thyroid state, and during illness. In this review we will briefly discuss recent developments in these different areas. These have resulted in the emerging view that the biological activity of thyroid hormone is regulated locally by tissue-specific regulation of the different deiodinases. HYROID HORMONE is essential for growth, development, thyrostatic drug 6-propyl-2-thiouracil (PTU). D1 activity is Tand regulation of energy metabolism (1–3). Amphibian positively regulated by T3, reflecting regulation of D1 ex- metamorphosis is an important example of thyroid hormone pression by T3 at the pretranslational level. actions on development (4). Equally well known is the crit- In humans, D2 activity is found in brain, anterior pitu- ical role of thyroid hormone in development and function itary, placenta, thyroid and skeletal muscle, and D2 mRNA of the human central nervous system (5,6). -
The Imprinted DLK1-MEG3 Gene Region on Chromosome 14Q32.2 Alters Susceptibility to Type 1 Diabetes
LETTERS The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes Chris Wallace, Deborah J Smyth, Meeta Maisuria-Armer, Neil M Walker, John A Todd & David G Clayton Genome-wide association (GWA) studies to map common score tests were based on the Cochran-Armitage test, with a Mantel disease susceptibility loci have been hugely successful, with extension to allow combination over different strata (UK region in over 300 reproducibly associated loci reported to date1. the case of the WTCCC and T1DGC samples, and estimated ancestry However, these studies have not yet provided convincing score derived from principal components in the case of the GoKinD- evidence for any susceptibility locus subject to parent-of-origin NIMH samples3). For imputed SNPs, we calculated the score statistics effects. Using imputation to extend existing GWA datasets2–4, using the expected value of the imputed SNP, given observed SNPs, we have obtained robust evidence at rs941576 for paternally with the expectation calculated under the null hypothesis. inherited risk of type 1 diabetes (T1D; ratio of allelic effects for Overall, there was some overdispersion of test statistics (λ = 1.14 and paternal versus maternal transmissions = 0.75; 95% confidence 1.09 for 1 and 2 degrees of freedom, respectively). This was consistent interval (CI) = 0.71–0.79). This marker is in the imprinted with the large sample size (almost 17,000 samples) and the overdisper- region of chromosome 14q32.2, which contains the functional sion observed in earlier analysis of these data without HapMap imputa- candidate gene DLK1. Our meta-analysis also provided support tion4. -
REVIEW Iodothyronine Deiodinase Structure and Function
189 REVIEW Iodothyronine deiodinase structure and function: from ascidians to humans Veerle M Darras and Stijn L J Van Herck Animal Physiology and Neurobiology Section, Department of Biology, Laboratory of Comparative Endocrinology, KU Leuven, Naamsestraat 61, PO Box 2464, B-3000 Leuven, Belgium (Correspondence should be addressed to V M Darras; Email: [email protected]) Abstract Iodothyronine deiodinases are important mediators of thyroid of each of them, however, varies amongst species, develop- hormone (TH) action. They are present in tissues throughout mental stages and tissues. This is especially true for 0 the body where they catalyse 3,5,3 -triiodothyronine (T3) amphibians, where the impact of D1 may be minimal. D2 production and degradation via, respectively, outer and inner and D3 expression and activity respond to thyroid status in ring deiodination. Three different types of iodothyronine an opposite and conserved way, while the response of D1 is deiodinases (D1, D2 and D3) have been identified in variable, especially in fish. Recently, a number of deiodinases vertebrates from fish to mammals. They share several have been cloned from lower chordates. Both urochordates common characteristics, including a selenocysteine residue and cephalochordates possess selenodeiodinases, although in their catalytic centre, but show also some type-specific they cannot be classified in one of the three vertebrate types. differences. These specific characteristics seem very well In addition, the cephalochordate amphioxus also expresses conserved for D2 and D3, while D1 shows more evolutionary a non-selenodeiodinase. Finally, deiodinase-like sequences diversity related to its Km, 6-n-propyl-2-thiouracil sensitivity have been identified in the genome of non-deuterostome and dependence on dithiothreitol as a cofactor in vitro. -
Imprinted Gene Expression at the Dlk1-Dio3 Cluster Is Controlled by Both Maternal and Paternal
bioRxiv preprint doi: https://doi.org/10.1101/536102; this version posted January 31, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Imprinted gene expression at the Dlk1-Dio3 cluster is controlled by both maternal and paternal IG-DMRs in a tissue-specific fashion. Katherine A. Alexander 2 and María J. García-García 1* 1 Department of Molecular Biology and Genetics, Cornell University. Ithaca. NY. 14853. USA 2 Current address: Department of Cellular and Developmental Biology, University of Pennsylvania. Philadelphia PA, 19103, USA * corresponding author: [email protected] Short title: Tissue-specific imprinting control Keywords: imprinting, TRIM28, IG-DMR, Dlk1, Gtl2, PRO-seq 1 bioRxiv preprint doi: https://doi.org/10.1101/536102; this version posted January 31, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. ABSTRACT Imprinting at the Dlk1-Dio3 cluster is controlled by the IG-DMR, an imprinting control region differentially methylated between maternal and paternal chromosomes. The maternal IG-DMR is essential for imprinting control, functioning as a cis enhancer element. Meanwhile, DNA methylation at the paternal IG-DMR is thought to prevent enhancer activity. To explore whether suppression of enhancer activity at the methylated IG-DMR requires the transcriptional repressor TRIM28, we analyzed Trim28chatwo embryos and performed epistatic experiments with IG-DMR deletion mutants. We found that while TRIM28 regulates the enhancer properties of the paternal IG-DMR, it also controls imprinting through other mechanisms. -
Targeting SARS-Cov-2 Entry Title
Genomics-guided identication of potential modulators of SARS-CoV-2 entry proteases, TMPRSS2 and Cathepsins B/L Kartikay Prasad Amity Institute of Neuropsychology & Neurosciences, Amity University, Noida Vijay Kumar ( [email protected] ) Amity Institute of Neuropsychology & Neurosciences, Amity University, Noida https://orcid.org/0000- 0002-3621-5025 Research Article Keywords: COVID-19, TMPRSS2, Cathepsins, gene set enrichment, estradiol, retinoic acid Posted Date: January 1st, 2021 DOI: https://doi.org/10.21203/rs.3.rs-138273/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Running Title: Targeting SARS-CoV-2 entry Title: Genomics-guided identification of potential modulators of SARS-CoV-2 entry proteases, TMPRSS2 and Cathepsins B/L Kartikay Prasad1, and Vijay Kumar1* 1Amity Institute of Neuropsychology & Neurosciences, Amity University, Noida, UP- 201303, India *Address for Correspondence Vijay Kumar, Ph. D. Assistant Professor Amity Institute of Neuropsychology & Neurosciences, Amity University, Noida, UP- 201313, India E-mail: [email protected] ORCID: 0000-0002-3621-5025 1 Abstract The entry of SARS-CoV-2 into host cells requires the activation of its spike protein by host cell proteases. The serine protease, transmembrane serine protease 2 (TMPRSS2) and cysteine proteases, cathepsins B, L (CTSB/L) activate spike protein and enabling SARS-CoV-2 entry to the host cell through two completely different and independent pathways. Given that the uncertainty of how SARS-CoV-2 infects and kills, the need for a deep understanding of SARS- CoV-2 biology is imperative. Herein, we performed genomic-guided meta-analysis to identify upstream regulatory elements altering the expression of TMPRSS2 and CTSB/L genes. -
Decreased Expression of the Thyroid Hormone-Inactivating Enzyme Type
www.nature.com/scientificreports OPEN Decreased expression of the thyroid hormone‑inactivating enzyme type 3 deiodinase is associated with lower survival rates in breast cancer Iuri Martin Goemann1, Vicente Rodrigues Marczyk1,5, Mariana Recamonde‑Mendoza2,3, Simone Magagnin Wajner1,5, Marcia Silveira Graudenz4,5 & Ana Luiza Maia 1,5* Thyroid hormones (THs) are critical regulators of cellular processes, while changes in their levels impact all the hallmarks of cancer. Disturbed expression of type 3 deiodinase (DIO3), the main TH‑inactivating enzyme, occurs in several human neoplasms and has been associated with adverse outcomes. Here, we investigated the patterns of DIO3 expression and its prognostic signifcance in breast cancer. DIO3 expression was evaluated by immunohistochemistry in a primary cohort of patients with breast cancer and validated in a second cohort using RNA sequencing data from the TCGA database. DNA methylation data were obtained from the same database. DIO3 expression was present in normal and tumoral breast tissue. Low levels of DIO3 expression were associated with increased mortality in the primary cohort. Accordingly, low DIO3 mRNA levels were associated with an increased risk of death in a multivariate model in the validation cohort. DNA methylation analysis revealed that the DIO3 gene promoter is hypermethylated in tumors when compared to normal tissue. In conclusion, DIO3 is expressed in normal and tumoral breast tissue, while decreased expression relates to poor overall survival in breast cancer patients. Finally, loss of DIO3 expression is associated with hypermethylation of the gene promoter and might have therapeutic implications. Breast cancer is the most common cancer in women worldwide, accounting for more than two million new cancer cases and 14.9% of all cancer-related deaths in women in 2018 1. -
DLK (DLK1) (NM 003836) Human Tagged ORF Clone Product Data
OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for RC202923 DLK (DLK1) (NM_003836) Human Tagged ORF Clone Product data: Product Type: Expression Plasmids Product Name: DLK (DLK1) (NM_003836) Human Tagged ORF Clone Tag: Myc-DDK Symbol: DLK1 Synonyms: Delta1; DLK; DLK-1; FA1; pG2; Pref-1; PREF1; ZOG Vector: pCMV6-Entry (PS100001) E. coli Selection: Kanamycin (25 ug/mL) Cell Selection: Neomycin ORF Nucleotide >RC202923 ORF sequence Sequence: Red=Cloning site Blue=ORF Green=Tags(s) TTTTGTAATACGACTCACTATAGGGCGGCCGGGAATTCGTCGACTGGATCCGGTACCGAGGAGATCTGCC GCCGCGATCGCC ATGACCGCGACCGAAGCCCTCCTGCGCGTCCTCTTGCTCCTGCTGGCTTTCGGCCACAGCACCTATGGGG CTGAATGCTTCCCGGCCTGCAACCCCCAAAATGGATTCTGCGAGGATGACAATGTTTGCAGGTGCCAGCC TGGCTGGCAGGGTCCCCTTTGTGACCAGTGCGTGACCTCTCCCGGCTGCCTTCACGGACTCTGTGGAGAA CCCGGGCAGTGCATTTGCACCGACGGCTGGGACGGGGAGCTCTGTGATAGAGATGTTCGGGCCTGCTCCT CGGCCCCCTGTGCCAACAACGGGACCTGCGTGAGCCTGGACGATGGCCTCTATGAATGCTCCTGTGCCCC CGGGTACTCGGGAAAGGACTGCCAGAAAAAGGACGGGCCCTGTGTGATCAACGGCTCCCCCTGCCAGCAC GGAGGCACCTGCGTGGATGATGAGGGCCGGGCCTCCCATGCCTCCTGCCTGTGCCCCCCTGGCTTCTCAG GCAATTTCTGCGAGATCGTGGCCAACAGCTGCACCCCCAACCCATGCGAGAACGACGGCGTCTGCACTGA CATCGGGGGCGACTTCCGCTGCCGGTGCCCAGCCGGCTTCATCGACAAGACCTGCAGCCGCCCGGTGACC AACTGCGCCAGCAGCCCGTGCCAGAACGGGGGCACCTGCCTGCAGCACACCCAGGTGAGCTACGAGTGTC TGTGCAAGCCCGAGTTCACAGGTCTCACCTGTGTCAAGAAGCGCGCGCTGAGCCCCCAGCAGGTCACCCG TCTGCCCAACGGCTATGGGCTGGCCTACCGCCTGACCCCTGGGGTGCACGAGCTGCCGGTGCAGCAGCCG -
Nonclassic Congenital Lipoid Adrenal Hyperplasia Diagnosed at 17 Months in a Korean Boy with Normal Male Genitalia: Emphasis on Pigmentation As a Diagnostic Clue
Case report https://doi.org/10.6065/apem.2020.25.1.46 Ann Pediatr Endocrinol Metab 2020;25:4651 Nonclassic congenital lipoid adrenal hyperplasia diagnosed at 17 months in a Korean boy with normal male genitalia: emphasis on pigmentation as a diagnostic clue Hosun Bae, MD1, Congenital lipoid adrenal hyperplasia (CLAH) is one of the most fatal conditions Min-Sun Kim, MD1, caused by an abnormality of adrenal and gonadal steroidogenesis. CLAH results Hyojung Park, MD1, from loss-of-function mutations of the steroidogenic acute regulatory (STAR) Ja-Hyun Jang, MD, PhD2, gene; the disease manifests with electrolyte imbalances and hyperpigmentation Jong-Moon Choi, MD, PhD2, in neonates or young infants due to adrenocortical hormone deficiencies, and 46, Sae-Mi Lee, MD, PhD2, XY genetic male CLAH patients can be phenotypically female. Meanwhile, some Sung Yoon Cho, MD, PhD1, patients with STAR mutations develop hyperpigmentation and mild signs of adrenal insufficiency, such as hypoglycemia, after infancy. These patients are classified as Dong-Kyu Jin, MD, PhD1 having nonclassic CLAH (NCCLAH) caused by STAR mutations that retain partial 1Department of Pediatrics, Samsung activity of STAR. We present the case of a Korean boy with normal genitalia who Medical Center, Sungkyunkwan Univer was diagnosed with NCCLAH. He presented with whole-body hyperpigmentation sity School of Medicine, Seoul, Korea and electrolyte abnormalities, which were noted at the age of 17 months after 2GC Genome, Yongin, Korea an episode of sepsis with peritonitis. The compound heterozygous mutations p.Gly221Ser and c.653C>T in STAR were identified by targeted gene-panel sequencing. Skin hyperpigmentation should be considered an important clue for diagnosing NCCLAH. -
Epigenomics Profiling Services
EPIGENOMICS PROFILING SERVICES • Chromatin analysis • DNA methylation analysis • RNA-seq analysis Diagenode helps you uncover the mysteries of epigenetics PAGE 3 Integrative epigenomics analysis DNA methylation analysis • Reduced representation bisulfite sequencing (RRBS) • Whole genome bisulfite sequencing analysis (WGBS) • Genome-wide DNA methylation • Differentially methylated region analysis DNA Chromatin RNA ChIP-seq/ChIP-qPCR analysis RNA-seq analysis • Histone modification ChIP-seq analysis • Small RNA-sequencing • Promoter analysis • mRNA analysis • Enhancer analysis • Whole transcriptome analysis • Transcription factor ChIP-seq analysis • Gene expression profiling • Customized NGS service • Chromatin accessibility (ATAC-seq) www.diagenode.com | PAGE 4 DIAGENODE EPIGENOMICS PROFILING SERVICES Expertise that you can trust Our Epigenomics Profiling Services assure the sample preparation expertise and quality data that you seek. We provide epigenome-wide analyses for understanding epigenetic mechanisms, epigenetics-related drug discovery, epigenetic biomarker identification, and functional epigenomics. Why Diagenode? • Expertise and trust: Recognized epigenetics leader, official partner of BLUEPRINT, IHEC and FAANG • Innovative technology: Utilization of the signature Bioruptor® sonication device for optimal chromatin and DNA shearing and the IP-Star® Automation device give reproducible and reliable optimization and results • Quality: Multiple QC steps in all workflows and validated antibodies plus reagents deliver superior data Human -
The Transition from Primary Colorectal Cancer to Isolated Peritoneal Malignancy
medRxiv preprint doi: https://doi.org/10.1101/2020.02.24.20027318; this version posted February 25, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . The transition from primary colorectal cancer to isolated peritoneal malignancy is associated with a hypermutant, hypermethylated state Sally Hallam1, Joanne Stockton1, Claire Bryer1, Celina Whalley1, Valerie Pestinger1, Haney Youssef1, Andrew D Beggs1 1 = Surgical Research Laboratory, Institute of Cancer & Genomic Science, University of Birmingham, B15 2TT. Correspondence to: Andrew Beggs, [email protected] KEYWORDS: Colorectal cancer, peritoneal metastasis ABBREVIATIONS: Colorectal cancer (CRC), Colorectal peritoneal metastasis (CPM), Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS & HIPEC), Disease free survival (DFS), Differentially methylated regions (DMR), Overall survival (OS), TableFormalin fixed paraffin embedded (FFPE), Hepatocellular carcinoma (HCC) ARTICLE CATEGORY: Research article NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 1 medRxiv preprint doi: https://doi.org/10.1101/2020.02.24.20027318; this version posted February 25, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . NOVELTY AND IMPACT: Colorectal peritoneal metastasis (CPM) are associated with limited and variable survival despite patient selection using known prognostic factors and optimal currently available treatments. -
Long-Term Follow-Up in a Chinese Child with Congenital Lipoid Adrenal
Zhao et al. BMC Endocrine Disorders (2018) 18:78 https://doi.org/10.1186/s12902-018-0307-6 CASEREPORT Open Access Long-term follow-up in a Chinese child with congenital lipoid adrenal hyperplasia due to a StAR gene mutation Xiu Zhao1,ZheSu1* , Xia Liu1,JianmingSong2,YungenGan3, Pengqiang Wen4,ShoulinLi5,LiWang1 and Lili Pan1 Abstract Background: Congenital lipoid adrenal hyperplasia (CLAH) is an extremely rare and the most severe form of congenital adrenal hyperplasia. Typical features include disorder of sex development, early-onset adrenal crisis and enlarged adrenal glands with fatty accumulation. Case presentation: We report a case of CLAH caused by mutations in the steroidogenic acute regulatory protein (StAR) gene. The patient had typical early-onset adrenal crisis at 2 months of age. She had normal-appearing female genitalia and a karyotype of 46, XY. The serum cortisol and adrenal steroids levels were always nearly undetectable, but the adrenocorticotropic hormone levels were extremely high. Genetic analysis revealed compound heterozygous mutations at c. 229C > T (p.Q77X) in exon 3 and c. 722C > T (p.Q258X) in exon 7 of the StAR gene. The former mutation was previously detected in only two other Chinese CLAH patients. Both mutations cause truncation of the StAR protein.Thecasereportedhereappearstobeaclassicexample of CLAH with very small adrenal glands and is the second reported CLAH case with small adrenal glands thus far. In a 15-year follow-up, the patient’sheight wasapproximatelyaverageforfemalesbeforeage4andfellto− 1 SDS at 10 years of age. Her bone age was similar to her chronological age from age 4 to age 15 years. Conclusions: In conclusion, this is a classic case of CLAH with exceptionally small adrenal glands.