scholarly journals Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation

2021 ◽  
Vol 7 (4) ◽  
pp. eabe2116
Author(s):  
David B. Beck ◽  
Mohammed A. Basar ◽  
Anthony J. Asmar ◽  
Joyce J. Thompson ◽  
Hirotsugu Oda ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Genomic Variation ◽  
Chromatin Remodelers ◽  
Histone Deacetylase 2 ◽  
Chromatin Regulators ◽  
Aberrant Gene Expression ◽  
Reversible Modification ◽  
Underlying Mechanisms ◽  
Aberrant Gene ◽  
Accessible Chromatin

Reversible modification of proteins with linkage-specific ubiquitin chains is critical for intracellular signaling. Information on physiological roles and underlying mechanisms of particular ubiquitin linkages during human development are limited. Here, relying on genomic constraint scores, we identify 10 patients with multiple congenital anomalies caused by hemizygous variants in OTUD5, encoding a K48/K63 linkage–specific deubiquitylase. By studying these mutations, we find that OTUD5 controls neuroectodermal differentiation through cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators (e.g., ARID1A/B, histone deacetylase 2, and HCF1), mutations of which underlie diseases that exhibit phenotypic overlap with OTUD5 patients. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. Our study describes a previously unidentified disorder we name LINKED (LINKage-specific deubiquitylation deficiency–induced Embryonic Defects) syndrome and reveals linkage-specific ubiquitin cleavage from chromatin remodelers as an essential signaling mode that coordinates chromatin remodeling during embryogenesis.

scholarly journals Publisher Correction to: C11orf95-RELA fusion drives aberrant gene expression through the unique epigenetic regulation for ependymoma formation

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Tatsuya Ozawa ◽  
Syuzo Kaneko ◽  
Frank Szulzewsky ◽  
Zhiwei Qiao ◽  
Mutsumi Takadera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epigenetic Regulation ◽  
Aberrant Gene Expression ◽  
Aberrant Gene

An amendment to this paper has been published and can be accessed via the original article.

scholarly journals H3K27 modifiers regulate lifespan in C. elegans in a context-dependent manner

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Abigail R. R. Guillermo ◽  
Karolina Chocian ◽  
Gavriil Gavriilidis ◽  
Julien Vandamme ◽  
Anna Elisabetta Salcini ◽  
...  
Keyword(s):  
Lifespan Extension ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Animal Cells ◽  
C Elegans ◽  
Specific Effects ◽  
Aberrant Gene Expression ◽  
Lysine Methyltransferase ◽  
Epigenetic Signatures ◽  
Aberrant Gene

Abstract Background Evidence of global heterochromatin decay and aberrant gene expression in models of physiological and premature ageing have long supported the “heterochromatin loss theory of ageing”, which proposes that ageing is aetiologically linked to, and accompanied by, a progressive, generalised loss of repressive epigenetic signatures. However, the remarkable plasticity of chromatin conformation suggests that the re-establishment of such marks could potentially revert the transcriptomic architecture of animal cells to a “younger” state, promoting longevity and healthspan. To expand our understanding of the ageing process and its connection to chromatin biology, we screened an RNAi library of chromatin-associated factors for increased longevity phenotypes. Results We identified the lysine demethylases jmjd-3.2 and utx-1, as well as the lysine methyltransferase mes-2 as regulators of both lifespan and healthspan in C. elegans. Strikingly, we found that both overexpression and loss of function of jmjd-3.2 and utx-1 are all associated with enhanced longevity. Furthermore, we showed that the catalytic activity of UTX-1, but not JMJD-3.2, is critical for lifespan extension in the context of overexpression. In attempting to reconcile the improved longevity associated with both loss and gain of function of utx-1, we investigated the alternative lifespan pathways and tissue specificity of longevity outcomes. We demonstrated that lifespan extension caused by loss of utx-1 function is daf-16 dependent, while overexpression effects are partially independent of daf-16. In addition, lifespan extension was observed when utx-1 was knocked down or overexpressed in neurons and intestine, whereas in the epidermis, only knockdown of utx-1 conferred improved longevity. Conclusions We show that the regulation of longevity by chromatin modifiers can be the result of the interaction between distinct factors, such as the level and tissue of expression. Overall, we suggest that the heterochromatin loss model of ageing may be too simplistic an explanation of organismal ageing when molecular and tissue-specific effects are taken into account.

scholarly journals Functional antagonism of chromatin modulators regulates epithelial-mesenchymal transition

2021 ◽  
Vol 7 (9) ◽  
pp. eabd7974
Author(s):  
Michela Serresi ◽  
Sonia Kertalli ◽  
Lifei Li ◽  
Matthias Jürgen Schmitt ◽  
Yuliia Dramaretska ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Developmental Process ◽  
Epithelial Mesenchymal Transition ◽  
Chromatin Remodelers ◽  
Mesenchymal Transition ◽  
Signature Genes ◽  
Chromatin Regulators ◽  
The Impact

Epithelial-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to modulate proliferation, migration, and stress response. Whereas kinase signaling is believed to be an EMT driver, the molecular mechanisms underlying epithelial-mesenchymal interconversion are incompletely understood. Here, we show that the impact of chromatin regulators on EMT interconversion is broader than that of kinases. By combining pharmacological modulation of EMT, synthetic genetic tracing, and CRISPR interference screens, we uncovered a minority of kinases and several chromatin remodelers, writers, and readers governing homeostatic EMT in lung cancer cells. Loss of ARID1A, DOT1L, BRD2, and ZMYND8 had nondeterministic and sometimes opposite consequences on epithelial-mesenchymal interconversion. Together with RNAPII and AP-1, these antagonistic gatekeepers control chromatin of active enhancers, including pan-cancer-EMT signature genes enabling supraclassification of anatomically diverse tumors. Thus, our data uncover general principles underlying transcriptional control of cancer cell plasticity and offer a platform to systematically explore chromatin regulators in tumor-state–specific therapy.

scholarly journals Transcriptome analysis identified aberrant gene expression in pollen developmental pathways leading to CGMS in cotton (Gossypium hirsutum L.)

PLoS ONE ◽  
2019 ◽  
Vol 14 (6) ◽  
pp. e0218381 ◽  
Author(s):  
Rasmieh Hamid ◽  
Hassan Marashi ◽  
Rukam S. Tomar ◽  
Saeid Malekzadeh Shafaroudi ◽  
Pritesh H. Sabara
Keyword(s):  
Gene Expression ◽  
Gossypium Hirsutum ◽  
Transcriptome Analysis ◽  
Developmental Pathways ◽  
Gossypium Hirsutum L ◽  
Aberrant Gene Expression ◽  
Aberrant Gene

Aberrant gene expression in cultured mammalian bone cells demonstrates an osteoblast defect in osteopetrosis

1994 ◽  
Vol 55 (3) ◽  
pp. 366-372 ◽  
Author(s):  
M. E. Jackson ◽  
V. Shalhoub ◽  
J. B. Lian ◽  
G. S. Stein ◽  
S. C. Marks
Keyword(s):  
Gene Expression ◽  
Bone Cells ◽  
Aberrant Gene Expression ◽  
Aberrant Gene ◽  
Mammalian Bone

scholarly journals Lineage promiscuity in hemopoietic differentiation and leukemia

Blood ◽  
1986 ◽  
Vol 67 (1) ◽  
pp. 1-11 ◽  
Author(s):  
MF Greaves ◽  
LC Chan ◽  
AJ Furley ◽  
SM Watt ◽  
HV Molgaard
Keyword(s):  
Gene Expression ◽  
Cell Receptor ◽  
Leukemic Cells ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Aberrant Gene Expression ◽  
Lineage Infidelity ◽  
T Cell Receptor Genes ◽  
Bona Fide ◽  
Aberrant Gene ◽  
Ig Heavy Chain

An increasing number of reports document instances in which individual leukemic cells coexpress markers normally believed to be restricted to a single lineage. This has been interpreted by McCulloch and colleagues as aberrant programming or lineage infidelity and contrasts with earlier suggestions that lineage fidelity of gene expression was usually maintained in leukemia. We argue that several examples of infidelity are suspect on technical grounds, whereas others are bona fide and require explanation, eg, partial rearrangements and expression of Ig heavy-chain and/or T cell receptor genes in inappropriate cells and terminal deoxynucleotidyl transferase in leukemic myeloblasts. Individual examples of truly aberrant gene expression may well occur in leukemia but with insufficient regularity to be of general significance. We suggest that verifiable and consistent examples of apparent lineage infidelity do not reflect genetic misprogramming but rather the existence of a transient phase of limited promiscuity of gene expression occurring in normal biopotential or multipotential progenitors and able to be preserved as a relic in leukemic blast cell populations that are in maturation arrest. This alternative explanation has interesting implications for mechanisms of hematopoietic differentiation and leads to some testable predictions.

Endometriosis

2019 ◽  
Author(s):  
Valerie A Flores ◽  
Hugh S Taylor
Keyword(s):  
Pelvic Pain ◽  
Treatment Options ◽  
Reproductive Age ◽  
Fertility Treatment ◽  
Future Research ◽  
Retrograde Menstruation ◽  
Reproductive Age Women ◽  
Aberrant Gene Expression ◽  
Aberrant Gene

Endometriosis is a chronic, gynecologic disease affecting 6 to 10% of reproductive age women. Pelvic pain, dyspareunia, and infertility are the most common symptoms of endometriosis that can have a significant impact on patients’ lives. Although the etiology remains largely unknown, the role of estrogens in the development and growth of endometriosis is well characterized. Medical and surgical therapies are the two cornerstones of endometriosis management. Following diagnosis of endometriosis, treatment options will be dependent on patient preference (ie, seeking pain relief versus fertility treatment). Future research aimed at targeting altered molecular pathways in patients with endometriosis will hopefully help mitigate the burden of this debilitating disease. This review contains 5 figures, 7 tables, and 75 references. Key Words: aberrant gene expression, altered immunity, endometriosis, infertility, medical and surgical therapy, pelvic pain, retrograde menstruation, stem cells

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