scholarly journals How protein methylation regulates steroid receptor function

2021 ◽  
Author(s):  
Lucie Malbeteau ◽  
Ha Thuy Pham ◽  
Louisane Eve ◽  
Michael R Stallcup ◽  
Coralie Poulard ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Steroid Receptors ◽  
Adult Life ◽  
Aberrant Expression ◽  
New Information ◽  
Important Regulator ◽  
Major Attention ◽  
Protein Methyltransferases ◽  
Neuronal Disorders ◽  
Receptor Family

Abstract Steroid receptors (SRs) are members of the nuclear hormonal receptor family, many of which are transcription factors regulated by ligand binding. SRs regulate various human physiological functions essential for maintenance of vital biological pathways, including development, reproduction and metabolic homeostasis. In addition, aberrant expression of SRs or dysregulation of their signaling has been observed in a wide variety of pathologies. SR activity is tightly and finely controlled by posttranslational modifications targeting the receptors and/or their coregulators. Whereas major attention has been focused on phosphorylation, growing evidence shows that methylation is also an important regulator of SRs. Interestingly, the protein methyltransferases depositing methyl marks are involved in many functions, from development to adult life. They have also been associated with pathologies such as inflammation, as well as cardiovascular and neuronal disorders, and cancer. This article provides an overview of SR methylation/demethylation events, along with their functional effects and biological consequences. An in depth understanding of the landscape of these methylation events could provide new information on SR regulation in physiology, as well as promising perspectives for the development of new therapeutic strategies, illustrated by the specific inhibitors of protein methyltransferases that are currently available.

scholarly journals Histone deacetylase (HDAC) 9: versatile biological functions and emerging roles in human cancer

2021 ◽  
Author(s):  
Chun Yang ◽  
Stéphane Croteau ◽  
Pierre Hardy
Keyword(s):  
Histone Deacetylase ◽  
Posttranslational Modifications ◽  
Histone Deacetylases ◽  
Muscle Development ◽  
Target Genes ◽  
Human Cancer ◽  
Expression Patterns ◽  
Aberrant Expression ◽  
Physiological Processes ◽  
Cancer Pathogenesis

Abstract Background HDAC9 (histone deacetylase 9) belongs to the class IIa family of histone deacetylases. This enzyme can shuttle freely between the nucleus and cytoplasm and promotes tissue-specific transcriptional regulation by interacting with histone and non-histone substrates. HDAC9 plays an essential role in diverse physiological processes including cardiac muscle development, bone formation, adipocyte differentiation and innate immunity. HDAC9 inhibition or activation is therefore a promising avenue for therapeutic intervention in several diseases. HDAC9 overexpression is also common in cancer cells, where HDAC9 alters the expression and activity of numerous relevant proteins involved in carcinogenesis. Conclusions This review summarizes the most recent discoveries regarding HDAC9 as a crucial regulator of specific physiological systems and, more importantly, highlights the diverse spectrum of HDAC9-mediated posttranslational modifications and their contributions to cancer pathogenesis. HDAC9 is a potential novel therapeutic target, and the restoration of aberrant expression patterns observed among HDAC9 target genes and their related signaling pathways may provide opportunities to the design of novel anticancer therapeutic strategies.

scholarly journals A Fresh Look at the Structure, Regulation, and Functions of Fodrin

2020 ◽  
Vol 40 (17) ◽  
Author(s):  
Jamuna S. Sreeja ◽  
Rince John ◽  
Dhrishya Dharmapal ◽  
Rohith Kumar Nellikka ◽  
Suparna Sengupta
Keyword(s):  
Posttranslational Modifications ◽  
Mammalian Cells ◽  
Structural Integrity ◽  
Cell Function ◽  
Cell Types ◽  
Erythroid Cell ◽  
Structural Variations ◽  
Neuronal Tissues ◽  
Different Cell Types ◽  
Neuronal Disorders

ABSTRACT Fodrin and its erythroid cell-specific isoform spectrin are actin-associated fibrous proteins that play crucial roles in the maintenance of structural integrity in mammalian cells, which is necessary for proper cell function. Normal cell morphology is altered in diseases such as various cancers and certain neuronal disorders. Fodrin and spectrin are two-chain (αβ) molecules that are encoded by paralogous genes and share many features but also demonstrate certain differences. Fodrin (in humans, typically a heterodimer of the products of the SPTAN1 and SPTBN1 genes) is expressed in nearly all cell types and is especially abundant in neuronal tissues, whereas spectrin (in humans, a heterodimer of the products of the SPTA1 and SPTB1 genes) is expressed almost exclusively in erythrocytes. To fulfill a role in such a variety of different cell types, it was anticipated that fodrin would need to be a more versatile scaffold than spectrin. Indeed, as summarized here, domains unique to fodrin and its regulation by Ca2+, calmodulin, and a variety of posttranslational modifications (PTMs) endow fodrin with additional specific functions. However, how fodrin structural variations and misregulated PTMs may contribute to the etiology of various cancers and neurodegenerative diseases needs to be further investigated.

scholarly journals Oxidative, Reductive, and Nitrosative Stress Effects on Epigenetics and on Posttranslational Modification of Enzymes in Cardiometabolic Diseases

2020 ◽  
Vol 2020 ◽  
pp. 1-19
Author(s):  
I. Pérez-Torres ◽  
M. E. Soto ◽  
V. Castrejón-Tellez ◽  
M. E. Rubio-Ruiz ◽  
L. Manzano Pech ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Nitrosative Stress ◽  
Adult Life ◽  
Antioxidant Systems ◽  
Amino Acid Residues ◽  
Cardiometabolic Diseases ◽  
Stress Effects ◽  
Cardiometabolic Disorders ◽  
Dna Reparation ◽  
The Impact

Oxidative (OS), reductive (RS), and nitrosative (NSS) stresses produce carbonylation, glycation, glutathionylation, sulfhydration, nitration, and nitrosylation reactions. OS, RS, and NSS are interrelated since RS results from an overactivation of antioxidant systems and NSS is the result of the overactivation of the oxidation of nitric oxide (NO). Here, we discuss the general characteristics of the three types of stress and the way by which the reactions they induce (a) damage the DNA structure causing strand breaks or inducing the formation of 8-oxo-d guanosine; (b) modify histones; (c) modify the activities of the enzymes that determine the establishment of epigenetic cues such as DNA methyl transferases, histone methyl transferases, acetyltransferases, and deacetylases; (d) alter DNA reparation enzymes by posttranslational mechanisms; and (e) regulate the activities of intracellular enzymes participating in metabolic reactions and in signaling pathways through posttranslational modifications. Furthermore, the three types of stress may establish new epigenetic marks through these reactions. The development of cardiometabolic disorders in adult life may be programed since early stages of development by epigenetic cues which may be established or modified by OS, RS, and NSS. Therefore, the three types of stress participate importantly in mediating the impact of the early life environment on later health and heritability. Here, we discuss their impact on cardiometabolic diseases. The epigenetic modifications induced by these stresses depend on union and release of chemical residues on a DNA sequence and/or on amino acid residues in proteins, and therefore, they are reversible and potentially treatable.

Notes on the elogium of a benefactor at Pompeii

2019 ◽  
Vol 32 ◽  
pp. 148-182
Author(s):  
John Bodel ◽  
Andreas Bendlin ◽  
Seth Bernard ◽  
Christer Bruun ◽  
Jonathan Edmondson
Keyword(s):  
Social History ◽  
Coming Of Age ◽  
Adult Life ◽  
Historical Event ◽  
The Road ◽  
New Information ◽  
Present Collection ◽  
History Of ◽  
Full Discussion ◽  
The Town

The rediscovery in the summer of 2017 of a large monumental tomb of unusual form outside the Stabian Gate at Pompeii caused an immediate sensation, and the swift initial publication by M. Osanna in JRA 31 (2018) of the long funerary inscription fronting the W side of the base, facing the road, has been welcomed gratefully by the scholarly community. The text — at 183 words, by far the longest funerary inscription yet found at Pompeii — records a series of extraordinary benefactions by an unnamed local worthy, beginning with a banquet held on the occasion of his coming-of-age ceremony and continuing, it seems, well into his adult life, up to the final years of the town when the monument was built. As Osanna and others have recognized, the inscription, which seems to allude to an historical event (Tac., Ann. 14.17), the riot between Nucerians and Pompeians around Pompeii’s amphitheater in A.D. 59, provides valuable if ambivalent new information relevant to the demographic, economic and social history of Pompeii that will require full discussion in a variety of contexts over time. The present collection of remarks, a collaborative effort, is offered in the spirit of debate and is intended as an interim contribution toward a more complete understanding of the text.1

DNA Methylation and Cancer

2004 ◽  
Vol 22 (22) ◽  
pp. 4632-4642 ◽  
Author(s):  
Partha M. Das ◽  
Rakesh Singal
Keyword(s):  
Dna Methylation ◽  
Histone Deacetylase Inhibitors ◽  
Promoter Regions ◽  
Methyl Transferase ◽  
Dietary Folate ◽  
Small Interference Rna ◽  
New Information ◽  
Important Regulator ◽  
Cancer Tissues ◽  
Methylation Patterns

DNA methylation is an important regulator of gene transcription, and its role in carcinogenesis has been a topic of considerable interest in the last few years. Alterations in DNA methylation are common in a variety of tumors as well as in development. Of all epigenetic modifications, hypermethylation, which represses transcription of the promoter regions of tumor suppressor genes leading to gene silencing, has been most extensively studied. However, global hypomethylation has also been recognized as a cause of oncogenesis. New information concerning the mechanism of methylation and its control has led to the discovery of many regulatory proteins and enzymes. The contribution of dietary folate and methylene terahydrofolate reductase polymorphisms to methylation patterns in normal and cancer tissues is under intense investigation. As methylation occurs early and can be detected in body fluids, it may be of potential use in early detection of tumors and for determining the prognosis. Because DNA methylation is reversible, drugs like 5′-azacytidine, decitabine, and histone deacetylase inhibitors are being used to treat a variety of tumors. Novel demethylating agents such as antisense DNA methyl transferase and small interference RNA are being developed, making the field of DNA methylation wider and more exciting.

scholarly journals Cohesin complex-associated holoprosencephaly

Brain ◽  
2019 ◽  
Vol 142 (9) ◽  
pp. 2631-2643 ◽  
Author(s):  
Paul Kruszka ◽  
Seth I Berger ◽  
Valentina Casa ◽  
Mike R Dekker ◽  
Jenna Gaesser ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
Genetic Diagnosis ◽  
Missense Variant ◽  
Cohesin Complex ◽  
Loss Of Function ◽  
Aberrant Expression ◽  
Human Neural Stem Cells ◽  
Forebrain Development ◽  
Important Regulator

Abstract Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80–90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.

scholarly journals Neonatal Exposure to Estradiol/Bisphenol A Alters Promoter Methylation and Expression of Nsbp1 and Hpcal1 Genes and Transcriptional Programs of Dnmt3a/b and Mbd2/4 in the RatProstate Gland Throughout Life

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 42-55 ◽  
Author(s):  
Wan-yee Tang ◽  
Lisa M. Morey ◽  
Yuk Yin Cheung ◽  
Lynn Birch ◽  
Gail S. Prins ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bisphenol A ◽  
Early Life ◽  
Precancerous Lesions ◽  
Adult Life ◽  
Epigenetic Reprogramming ◽  
Neonatal Exposure ◽  
Epigenetic Mark ◽  
Aberrant Expression ◽  
Epigenetic Marks

Evidence supporting an early origin of prostate cancer is growing. We demonstrated previously that brief exposure of neonatal rats to estradiol or bisphenol A elevated their risk of developing precancerous lesions in the prostate upon androgen-supported treatment with estradiol as adults. Epigenetic reprogramming may be a mechanism underlying this inductive event in early life, because we observed overexpression of phosphodiesterase 4D variant 4 (Pde4d4) through induction of hypomethylation of its promoter. This epigenetic mark was invisible in early life (postnatal d 10), becoming apparent only after sexual maturation. Here, we asked whether other estrogen-reprogrammable epigenetic marks have similar or different patterns in gene methylation changes throughout life. We found that hypomethylation of the promoter of nucleosome binding protein-1 (Nsbp1), unlike Pde4d4, is an early and permanent epigenetic mark of neonatal exposure to estradiol/bisphenol A that persists throughout life, unaffected by events during adulthood. In contrast, hippocalcin-like 1 (Hpcal1) is a highly plastic epigenetic mark whose hypermethylation depends on both type of early-life exposure and adult-life events. Four of the eight genes involved in DNA methylation/demethylation showed early and persistent overexpression that was not a function of DNA methylation at their promoters, including genes encoding de novo DNA methyltransferases (Dnmt3a/b) and methyl-CpG binding domain proteins (Mbd2/4) that have demethylating activities. Their lifelong aberrant expression implicates them in early-life reprogramming and prostate carcinogenesis during adulthood. We speculate that the distinctly different fate of early-life epigenetic marks during adulthood reflects the complex nature of lifelong editing of early-life epigenetic reprogramming.

scholarly journals S-Palmitoylation of Synaptic Proteins as a Novel Mechanism Underlying Sex-Dependent Differences in Neuronal Plasticity

2021 ◽  
Vol 22 (12) ◽  
pp. 6253
Author(s):  
Monika Zaręba-Kozioł ◽  
Anna Bartkowiak-Kaczmarek ◽  
Matylda Roszkowska ◽  
Krystian Bijata ◽  
Izabela Figiel ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Steroid Receptors ◽  
Protein S ◽  
Neuronal Morphology ◽  
Synaptic Proteins ◽  
Biological Processes ◽  
Molecular Signaling ◽  
Membrane Excitability ◽  
Brain Functioning ◽  
The Brain

Although sex differences in the brain are prevalent, the knowledge about mechanisms underlying sex-related effects on normal and pathological brain functioning is rather poor. It is known that female and male brains differ in size and connectivity. Moreover, those differences are related to neuronal morphology, synaptic plasticity, and molecular signaling pathways. Among different processes assuring proper synapse functions are posttranslational modifications, and among them, S-palmitoylation (S-PALM) emerges as a crucial mechanism regulating synaptic integrity. Protein S-PALM is governed by a family of palmitoyl acyltransferases, also known as DHHC proteins. Here we focused on the sex-related functional importance of DHHC7 acyltransferase because of its S-PALM action over different synaptic proteins as well as sex steroid receptors. Using the mass spectrometry-based PANIMoni method, we identified sex-dependent differences in the S-PALM of synaptic proteins potentially involved in the regulation of membrane excitability and synaptic transmission as well as in the signaling of proteins involved in the structural plasticity of dendritic spines. To determine a mechanistic source for obtained sex-dependent changes in protein S-PALM, we analyzed synaptoneurosomes isolated from DHHC7-/- (DHHC7KO) female and male mice. Our data showed sex-dependent action of DHHC7 acyltransferase. Furthermore, we revealed that different S-PALM proteins control the same biological processes in male and female synapses.

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