Article
Multidisciplinary Sciences
Nicholas J. Fuda, Katjusa Brejc, William S. Kruesi, Edward J. Ralston, Rachel Bigley, Aram Shin, Miki Okada, Barbara J. Meyer
Summary: The study identifies critical X-sequence motifs in Caenorhabditis elegans that act synergistically in hermaphrodites to direct X-specific recruitment of the dosage compensation complex (DCC), a condensin complex. The findings reveal that synergy in DCC binding via combinatorial clustering of motifs triggers DCC assembly specifically on X chromosomes.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biology
Qiming Yang, Te-Wen Lo, Katjusa Brejc, Caitlin Schartner, Edward J. Ralston, Denise M. Lapidus, Barbara J. Meyer
Summary: An evolutionary perspective reveals that the genetic regulatory hierarchy controlling sex determination and X-chromosome dosage compensation is conserved but with divergent mechanisms between Caenorhabditis briggsae and Caenorhabditis elegans. While the binding of the specialized condensin dosage compensation complex (DCC) to recruitment sites in Cbr is additive, DCC binding to Cel recruitment sites is synergistic. Rapid divergence of DCC target specificity, determined by motifs, has played a crucial role in establishing reproductive isolation between nematode species.
Article
Biology
Jun Kim, David S. Jimenez, Bhavana Ragipani, Bo Zhang, Lena A. Street, Maxwell Kramer, Sarah E. Albritton, Lara H. Winterkorn, Ana K. Morao, Sevinc Ercan, Jessica K. Tyler
Summary: Condensins are molecular motors that compact DNA via linear translocation. In Caenorhabditis elegans, a specialized condensin on the X-chromosome participates in dosage compensation and the formation of topologically associating domains (TADs). The recruitment and spreading of condensin from specific recruitment elements (rex) on the X-chromosome are necessary and sufficient for the formation of TADs. However, the insertion of rex elements on autosomes does not lead to TAD formation unless multiple rex sites are present. Therefore, rex sites act as loading sites and bidirectional barriers for condensin dosage compensation, playing a crucial role in the formation of TADs.
Article
Genetics & Heredity
Bhavana Ragipani, Sarah Elizabeth Albritton, Ana Karina Morao, Diogo Mesquita, Maxwell Kramer, Sevinc Ercan
Summary: This study found that Caenorhabditis elegans can tolerate increased gene dosage, but lacks a genome-wide dosage compensation mechanism at the mRNA level. Different genes within chromosomal duplications show variable levels of mRNA increase, indicating feedback regulation. Somatic dosage compensation and germline repression reduce the mRNA increase from X chromosomal duplications.
G3-GENES GENOMES GENETICS
(2022)
Article
Biotechnology & Applied Microbiology
Irene Talon, Adrian Janiszewski, Bart Theeuwes, Thomas Lefevre, Juan Song, Greet Bervoets, Lotte Vanheer, Natalie De Geest, Suresh Poovathingal, Ryan Allsop, Jean-Christophe Marine, Florian Rambow, Thierry Voet, Vincent Pasque
Summary: Our study reveals that intrinsic compensatory mechanisms exist in mammalian cells, involving modulation of chromatin accessibility to counteract imbalances in gene dosage between the X chromosome and autosomes caused by evolutionary changes or X chromosome inactivation in vitro. Through genome-wide approaches, allele-specific ATAC-seq, and single-cell RNA-seq, we demonstrate increased chromatin accessibility on the upregulated active X chromosome compared to autosomes in female embryonic fibroblasts and during reprogramming to pluripotency. Additionally, our data show that ZFP42/REX1, a gene associated with pluripotency that evolved specifically in placental mammals, targets multiple X-linked genes, suggesting an evolutionary link between ZFP42/REX1, X chromosome reactivation, and pluripotency.
Review
Biochemistry & Molecular Biology
Yuri Y. Shevelyov, Sergey Ulianov, Mikhail S. Gelfand, Stepan N. Belyakin, Sergey Razin
Summary: Dosage compensation ensures equal gene expression between a single male X chromosome and the pairs of autosomes and female X chromosomes. In fruit flies, canonical dosage compensation is achieved through the action of the male-specific lethal (MSL) complex in all male somatic cells. This complex contains the acetyl transferase males absent on the first (MOF), which specifically hyperacetylates H4K16 on the male X chromosome, promoting transcription of X-linked genes. Additionally, there is growing evidence for the existence of non-canonical dosage compensation mechanisms in somatic and germline cells.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Genetics & Heredity
Mette Viuff, Anne Skakkebaek, Emma B. Johannsen, Simon Chang, Steen Bonlykke Pedersen, Katrine Meyer Lauritsen, Mette Glavind Bulow Pedersen, Christian Trolle, Jesper Just, Claus H. Gravholt
Summary: This study comprehensively analyzed the effects of the X chromosome number on the transcriptome and methylome in blood, fat, and muscle tissue of individuals with sex chromosome aneuploidies (SCAs). It was found that X chromosome number globally affected the transcriptome and methylome in a tissue-specific manner. The study also identified different gene expression and methylation patterns between 45,X and 47,XXY, and observed a significant effect of sex in fat and muscle tissue. Additionally, the study found regulatory functions of Y chromosomal genes on X chromosomal genes.
Article
Cell Biology
Joanna M. Wenda, Reinier F. Prosee, Caroline Gabus, Florian A. Steiner
Summary: Centromeres are crucial regions on chromosomes for kinetochore formation and microtubule attachment during mitosis. In the nematode C. elegans, the loading factor KNL-2 plays a key role in CENP-A deposition. Phosphorylation of KNL-2 by CDK-1 regulates the cooperation between centromeres and the condensation machinery, impacting chromosome segregation and condensation levels.
JOURNAL OF CELL SCIENCE
(2021)
Article
Genetics & Heredity
Michael B. Davis, Eshna Jash, Bahaar Chawla, Rebecca A. Haines, Lillian E. Tushman, Ryan Troll, Gyorgyi Csankovszki
Summary: Dosage compensation is a crucial gene regulatory mechanism that affects chromatin structure and is essential for organismal health. In this study, Argonaute genes were identified as promoters of dosage compensation in Caenorhabditis elegans. These genes not only impact gene expression but also influence the condensation of the X chromosomes.
Review
Genetics & Heredity
Barbara J. Meyer
Summary: Abnormalities in chromosome number can disrupt gene expression balance and decrease fitness. The difference in X-chromosome dose used to determine sexual fate is well tolerated across species. The nematode Caenorhabditis elegans provides insights into the chromosome counting and dosage compensation mechanisms and how small quantitative differences in signals can lead to different fates. Understanding X-chromosome dosage compensation reveals the interplay between chromatin modification and chromosome structure in regulating gene expression.
Article
Multidisciplinary Sciences
Leah F. Rosin, Dahong Chen, Yang Chen, Elissa P. Lei
Summary: Research on the chromatin structure in the silkmoth, Bombyx mori, reveals that the two male sex chromosomes are equally downregulated after dosage compensation (DC) is established. In females, the Z chromosome chromatin becomes more accessible and repositions towards the nuclear center during the early stages of DC. This study also uncovers intriguing similarities between DC mechanisms in B. mori and C. elegans, despite having evolutionarily distinct sex chromosomes, suggesting a possible role for holocentricity in DC mechanisms.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Ryoma Ota, Makoto Hayashi, Shumpei Morita, Hiroki Miura, Satoru Kobayashi
Summary: Dosage compensation equalizes sex chromosome gene expression between the sexes in Drosophila, achieved by the male-specific lethal (MSL) complex in somatic cells. However, it remains unclear whether dosage compensation occurs in germline cells. Transcriptome analysis showed higher expression of X-linked genes in female primordial germ cells (PGCs) compared to males, with absence of H4K16ac due to failure of MSL complex formation in male PGCs.
SCIENTIFIC REPORTS
(2021)
Review
Biotechnology & Applied Microbiology
Zhou Li, He Yang, Yifei Wang, Shan-Ho Chou, Jin He
Summary: This article introduces the critical role of microbial cell factories in green biomanufacturing. It proposes the concept of the "spatial position effect" and uses 3D genomics technology to study the spatial structure characteristics of the chassis strain's 3D genome. It also suggests a method to design integration sites for synthetic gene circuits and achieve stable and efficient chassis strains for green biomanufacturing.
TRENDS IN BIOTECHNOLOGY
(2022)
Article
Cell Biology
Lauren Forbes Beadle, Hongpeng Zhou, Magnus Rattray, Hilary L. Ashe
Summary: Dosage compensation in Drosophila involves hypertranscription of the male X chromosome, which is critical for balancing X-linked gene expression between sexes and to the autosomes. By analyzing quantitative live imaging data, researchers found that the four X chromosome genes studied undergo transcriptional bursting in both male and female embryos. Mechanistically, the upregulation of male X chromosome genes is primarily mediated by higher initiation rates and burst amplitudes, while burst frequency is spatially modulated within the expression domain. These findings illustrate how distinct burst parameters are regulated to establish the complex transcriptional outputs underlying developmental patterning.
Article
Multidisciplinary Sciences
Hemant Chandru Naik, Kishore Hari, Deepshikha Chandel, Susmita Mandal, Mohit Kumar Jolly, Srimonta Gayen
Summary: Recent studies have shown the widespread presence of dynamic random monoallelic expression of autosomal genes during pregastrulation. The coordination of allelic bursting is lineage specific, with genes regulating development showing higher levels of coordination. This provides significant insights into the prevalence and origin of dynamic aRME during early development.
Article
Hematology
Birgit Van Dooijeweert, Melissa H. Broeks, Nanda M. Verhoeven-Duif, Eduard J. Van Beers, Edward E. S. Nieuwenhuis, Wouter W. Van Solinge, Marije Bartels, Judith J. Jans, Richard Van Wijk
Summary: The study found that untargeted metabolomics in dried blood spots can be used to diagnose pyruvate kinase deficiency, achieving high performance through its unique metabolic fingerprint and a classification model designed with machine learning algorithms.
Article
Biochemistry & Molecular Biology
Beau Olivier van Driel, Maike Schuldt, Sila Algul, Evgeni Levin, Ahmet Guclu, Tjeerd Germans, Albert C. van Rossum, Jiayi Pei, Magdalena Harakalova, Annette Baas, Judith J. M. Jans, Jolanda van der Velden
Summary: The study utilized metabolomics profiling to analyze CAVD and AS, revealing a 30 metabolic profile that can distinguish AS patients from healthy controls, with metabolites related to nitric oxide metabolism and inflammation. Additionally, the experiment indicated that these metabolites may be linked to left ventricular remodeling and serve as potential blood biomarkers for AS diagnosis and timing of intervention.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Endocrinology & Metabolism
Melissa H. Broeks, Clara D. M. van Karnebeek, Ronald J. A. Wanders, Judith J. M. Jans, Nanda M. Verhoeven-Duif
Summary: The malate aspartate shuttle (MAS) is crucial for mitochondrial respiration and maintaining cytosolic redox balance, playing a key role in sustaining metabolic pathways like glycolysis and serine biosynthesis. Five potential MAS deficiencies have been reported, mostly presenting with infantile epileptic encephalopathy. Biochemical characteristics such as high lactate, disturbed redox balance, and low serine can aid in diagnosis, while treatment options include a ketogenic diet, serine, and vitamin B6 supplementation.
JOURNAL OF INHERITED METABOLIC DISEASE
(2021)
Article
Biochemistry & Molecular Biology
Kristina Krassovsky, Rajarshi P. Ghosh, Barbara J. Meyer
Summary: The study revealed high levels of negative supercoiling at transcription start sites in Caenorhabditis elegans embryos, but dramatic reductions in negative supercoiling at transcription start sites in diapause larvae, indicating developmental-stage-specific regulation. Furthermore, the research found that DNA structure plays a critical role in chromosome architecture and gene expression.
Article
Endocrinology & Metabolism
Vivian Lehmann, Imre F. Schene, Arif I. Ardisasmita, Nalan Liv, Tineke Veenendaal, Judith Klumperman, Hubert P. J. van der Doef, Henkjan J. Verkade, Monique M. A. Verstegen, Luc J. W. van der Laan, Judith J. M. Jans, Nanda M. Verhoeven-Duif, Peter M. van Hasselt, Edward E. S. Nieuwenhuis, Bart Spee, Sabine A. Fuchs
Summary: Inborn errors of metabolism are a group of monogenic disorders affecting metabolic pathways, leading to accumulation or deficit of intermediate metabolites causing disease phenotypes. Patient-derived liver-derived ICOs show potential for in vitro modeling and personalized drug testing for IEMs, but their application range and limitations need further investigation.
JOURNAL OF INHERITED METABOLIC DISEASE
(2022)
Review
Genetics & Heredity
Barbara J. Meyer
Summary: Abnormalities in chromosome number can disrupt gene expression balance and decrease fitness. The difference in X-chromosome dose used to determine sexual fate is well tolerated across species. The nematode Caenorhabditis elegans provides insights into the chromosome counting and dosage compensation mechanisms and how small quantitative differences in signals can lead to different fates. Understanding X-chromosome dosage compensation reveals the interplay between chromatin modification and chromosome structure in regulating gene expression.
Article
Cell Biology
Maike Schuldt, Beau van Driel, Sila Alguel, Rahana Y. Parbhudayal, Daniela Q. C. M. Barge-Schaapveld, Ahmet Gueclue, Mark Jansen, Michelle Michels, Annette F. Baas, Mark A. van de Wiel, Max Nieuwdorp, Evgeni Levin, Tjeerd Germans, Judith J. M. Jans, Jolanda van der Velden
Summary: This study identified unique metabolic signatures in the serum of preclinical carriers and patients with hypertrophic cardiomyopathy, which could potentially be used for risk stratification and precision therapeutics for the disease.
Letter
Hematology
Myrthe J. van Dijk, Minke A. E. Rab, Brigitte A. van Oirschot, Jennifer Bos, Cleo Derichs, Anita W. Rijneveld, Marjon H. Cnossen, Erfan Nur, Bart J. Biemond, Marije Bartels, Judith J. M. Jans, Wouter W. van Solinge, Roger E. G. Schutgens, Richard van Wijk, Eduard J. van Beers
AMERICAN JOURNAL OF HEMATOLOGY
(2022)
Article
Cell Biology
Barbara J. Meyer
Summary: Abnormalities in chromosome dose can reduce organismal fitness and viability, but differences in X-chromosome dose determining sex are well tolerated. Various species have evolved mechanisms to balance X-chromosome gene expression between sexes. The mechanism underlying nematode X-chromosome counting and dosage compensation reveals how small quantitative differences in molecular signals translate into different developmental fates. Additionally, the dosage-compensation complex also regulates lifespan and tolerance to proteotoxic stress.
CURRENT OPINION IN GENETICS & DEVELOPMENT
(2022)
Article
Psychiatry
Dorinde Korteling, Marco P. Boks, Ania M. Fiksinski, Ilja N. van Hoek, Jacob A. S. Vorstman, Nanda M. Verhoeven-Duif, Judith J. M. Jans, Janneke R. Zinkstok
Summary: The 22q11.2 deletion syndrome (22q11.2DS) is associated with increased risk of autism spectrum disorders (ASD) and intellectual impairment, potentially due to deficits in early brain development metabolic processes. This study identified a unique metabolic signature for 22q11.2DS and trait-specific metabolomic patterns related to intelligence and ASD within the patients. These findings provide insights into the biological mechanisms underlying the neurodevelopmental phenotype and may contribute to the identification of therapeutic targets for developmental disorders.
TRANSLATIONAL PSYCHIATRY
(2022)
Article
Multidisciplinary Sciences
Nicholas J. Fuda, Katjusa Brejc, William S. Kruesi, Edward J. Ralston, Rachel Bigley, Aram Shin, Miki Okada, Barbara J. Meyer
Summary: The study identifies critical X-sequence motifs in Caenorhabditis elegans that act synergistically in hermaphrodites to direct X-specific recruitment of the dosage compensation complex (DCC), a condensin complex. The findings reveal that synergy in DCC binding via combinatorial clustering of motifs triggers DCC assembly specifically on X chromosomes.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biology
Qiming Yang, Te-Wen Lo, Katjusa Brejc, Caitlin Schartner, Edward J. Ralston, Denise M. Lapidus, Barbara J. Meyer
Summary: An evolutionary perspective reveals that the genetic regulatory hierarchy controlling sex determination and X-chromosome dosage compensation is conserved but with divergent mechanisms between Caenorhabditis briggsae and Caenorhabditis elegans. While the binding of the specialized condensin dosage compensation complex (DCC) to recruitment sites in Cbr is additive, DCC binding to Cel recruitment sites is synergistic. Rapid divergence of DCC target specificity, determined by motifs, has played a crucial role in establishing reproductive isolation between nematode species.
Article
Biochemistry & Molecular Biology
Melanie T. Achleitner, Judith J. M. Jans, Laura Ebner, Johannes Spenger, Vassiliki Konstantopoulou, Rene G. Feichtinger, Karin Brugger, Doris Mayr, Ron A. Wevers, Christian Thiel, Saskia B. Wortmann, Johannes A. Mayr
Summary: Two siblings showed increased levels of galactose and related metabolites in neonatal screening, but diagnostic tests did not identify abnormalities in known disease-causing enzymes. Whole-exome sequencing revealed a homozygous missense variant in the PPA1 gene, which was found to reduce enzyme activity and protein stability. The observed metabolic derangement is hypothesized to be a mild manifestation of PPA1 deficiency.
Letter
Hematology
Birgit van Dooijeweert, Melissa H. Broeks, Nanda M. Verhoeven-Duif, Wouter W. van Solinge, Eduard J. van Beers, Minke A. E. Rab, Edward E. S. Nieuwenhuis, Judith J. M. Jans, Marije Bartels, Richard van Wijk
Article
Genetics & Heredity
Shereen G. Ghosh, Sangmoon Lee, Rudy Fabunan, Guoliang Chai, Maha S. Zaki, Ghada Abdel-Salam, Tipu Sultan, Tawfeg Ben-Omran, Javeria Raza Alvi, Jennifer McEvoy-Venneri, Valentina Stanley, Aakash Patel, Danica Ross, Jeffrey Ding, Mohit Jain, Daqiang Pan, Philipp Luebbert, Bernd Kammerer, Nils Wiedemann, Nanda M. Verhoeven-Duif, Judith J. Jans, David Murphy, Mehran Beiraghi Toosi, Farah Ashrafzadeh, Shima Imannezhad, Ehsan Ghayoor Karimiani, Khalid Ibrahim, Elizabeth R. Waters, Reza Maroofian, Joseph G. Gleeson
Summary: The study reveals that mutations in HPDL are associated with a unique neurometabolic mitochondrial infantile neurodegenerative condition in humans, based on evidence of apoptosis in cellular lineages and metabolic profiling.
GENETICS IN MEDICINE
(2021)