A noncanonical role of roX RNAs in autosomal epigenetic repression

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 2, 2025

Long noncoding RNAs known as roX (RNA on the X) are crucial for male development in Drosophila, their loss leads to lethality from late larval stages. While recognized role sex-chromosome dosage compensation, ensuring balanced expression of X-linked genes both sexes, potential influence autosomal gene regulation remains unexplored. Here, using an integrative multi-omics approach, we show that not only govern X chromosome but also target autosomes lack male-specific lethal (MSL) complex occupancy, together with Polycomb repressive complexes (PRCs). We observed colocalize MSL proteins and PRC components autosomes. Intriguingly, function reduces X-chromosomal H4K16ac levels H3K27me3 levels. Correspondingly, display reduced expression, whereas many exhibit elevated upon loss. Our findings propose a dual RNAs: activators repressors genes, achieved through interactions complexes, respectively. This study uncovers unconventional epigenetic interaction. Drosophila. authors regulating at specific loci, working coordination

Language: Английский

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Activation of Xist by an evolutionarily conserved function of KDM5C demethylase

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: May 11, 2022

Abstract XX female and XY male therian mammals equalize X-linked gene expression through the mitotically-stable transcriptional inactivation of one two X chromosomes in somatic cells. Here, we describe an essential function homolog ancestral X-Y pair, Kdm5c - Kdm5d , Xist lncRNA, which is required for stable X-inactivation. Ablation females results a significant reduction RNA expression. encodes demethylase that enhances by converting histone H3K4me2/3 modifications into H3K4me1. Ectopic mouse human KDM5C but not Y-linked KDM5D induces embryonic stem cells (mESCs). Similarly, marsupial (opossum) also upregulates mESCs, despite marsupials lacking suggesting activates eutherians strongly conserved predates divergence eutherian metatherian mammals. In support, prototherian (platypus) mESCs. Together, our data suggest co-opted during sex chromosome evolution to upregulate female-specific induction

Language: Английский

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The SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 11, 2023

Abstract The heptad repeats of the C-terminal domain (CTD) RNA polymerase II (Pol II) are extensively modified throughout transcription cycle. CTD coordinates synthesis and processing by recruiting regulators as well capping, splicing 3’end factors. SPOC PHF3 was recently identified a reader specifically binding to phosphorylated serine-2 residues in adjacent repeats. Here, we establish domains human proteins DIDO, SHARP (also known SPEN) RBM15 phosphoserine modules that can act readers but also recognize other partners. We report crystal structure complex with identify molecular determinants for its specific serine-5. DIDO preferentially interact Pol elongation complex, while engage writers m 6 A, most abundant modification. positively regulates A levels mRNA stability SPOC-dependent manner, is essential localization inactive X-chromosomes. Our findings suggest major interface between machinery co-transcriptional processes.

Language: Английский

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A model for organization and regulation of nuclear condensates by gene activity

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 12, 2023

Abstract Condensation by phase separation has recently emerged as a mechanism underlying many nuclear compartments essential for cellular functions. Nuclear condensates enrich nucleic acids and proteins, localize to specific genomic regions, often promote gene expression. How diverse properties of are shaped organization activity is poorly understood. Here, we develop physics-based model interrogate how spatially-varying transcription impacts condensate dynamics. Our predicts that spatial clustering active genes can enable precise localization de novo nucleation condensates. Strong high results in aspherical morphologies. Condensates flow towards distant clusters competition between multiple lead stretched morphologies activity-dependent repositioning. Overall, our recapitulates morphological dynamical features offers unified mechanistic framework study the interplay non-equilibrium processes, transcription, multicomponent cell biology.

Language: Английский

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Chromosomal and environmental contributions to sex differences in the vulnerability to neurological and neuropsychiatric disorders: Implications for therapeutic interventions

Progress in Neurobiology, Journal Year: 2022, Volume and Issue: 219, P. 102353 - 102353

Published: Sept. 12, 2022

Neurological and neuropsychiatric disorders affect men women differently. Multiple sclerosis, Alzheimer's disease, anxiety disorders, depression, meningiomas late-onset schizophrenia more frequently than men. By contrast, Parkinson's autism spectrum condition, attention-deficit hyperactivity disorder, Tourette's syndrome, amyotrophic lateral sclerosis early-onset are prevalent in Women have been historically under-recruited or excluded from clinical trials, most basic research uses male rodent cells animals as disease models, rarely studying both sexes factoring sex a potential source of variation, resulting poor understanding the underlying biological reasons for gender differences development such diseases. Putative pathophysiological contributors include hormones epigenetics regulators but additional non-biological influences may be at play. We review here evidence underpinning role chromosome complement, X inactivation, environmental epigenetic vulnerability to brain disease. conclude that there is pressing need better genetic, mechanisms sustaining diseases, which critical developing precision medicine approach based on sex-tailored prevention treatment.

Language: Английский

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Regulatory principles and mechanisms governing the onset of random X-chromosome inactivation

Current Opinion in Genetics & Development, Journal Year: 2023, Volume and Issue: 81, P. 102063 - 102063

Published: June 24, 2023

X-chromosome inactivation (XCI) has evolved in mammals to compensate for the difference X-chromosomal dosage between sexes. In placental mammals, XCI is initiated during early embryonic development through upregulation of long noncoding RNA Xist from one randomly chosen X chromosome each female cell. The locus must thus integrate both X-linked and developmental trans-regulatory factors a dosage-dependent manner. Furthermore, two alleles coordinate ensure exactly per this review, we summarize regulatory principles that govern onset XCI. We go on provide an overview over have been implicated regulation discuss recent advances our understanding how Xist's cis-regulatory landscape integrates information precise fashion.

Language: Английский

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Transcriptomics for Clinical and Experimental Biology Research: Hang on a Seq

Advanced Genetics, Journal Year: 2023, Volume and Issue: 4(2)

Published: Jan. 17, 2023

Sequencing the human genome empowers translational medicine, facilitating transcriptome-wide molecular diagnosis, pathway biology, and drug repositioning. Initially, microarrays are used to study bulk transcriptome; but now short-read RNA sequencing (RNA-seq) predominates. Positioned as a superior technology, that makes discovery of novel transcripts routine, most RNA-seq analyses in fact modeled on known transcriptome. Limitations methodology have emerged, while design of, analysis strategies applied to, arrays matured. An equitable comparison between these technologies is provided, highlighting advantages modern hold over RNA-seq. Array protocols more accurately quantify constitutively expressed protein coding genes across tissue replicates, reliable for studying lower genes. Arrays reveal long noncoding RNAs (lncRNA) neither sparsely nor than Heterogeneous coverage observed with RNA-seq, undermines validity reproducibility analyses. The factors driving observations, many which relevant long-read or single-cell discussed. As proposed herein, reappreciation transcriptomic methods required, including wider use high-density array data-to urgently revise existing anatomical reference atlases assist accurate lncRNAs.

Language: Английский

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An RNA-centric view of transcription and genome organization

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(19), P. 3627 - 3643

Published: Oct. 1, 2024

Language: Английский

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Orchestrating Asymmetric Expression: Mechanisms behind Xist Regulation

Epigenomes, Journal Year: 2024, Volume and Issue: 8(1), P. 6 - 6

Published: Feb. 1, 2024

Compensation for the gene dosage disequilibrium between sex chromosomes in mammals is achieved female cells by repressing one of its X through a process called chromosome inactivation (XCI), exemplifying control expression epigenetic mechanisms. A critical player this mechanism Xist, long, non-coding RNA upregulated from single during early embryonic development cells. Over past few decades, many factors involved at different levels regulation Xist have been discovered. In review, we hierarchically describe and analyze layers operating concurrently intricately interacting with each other to achieve asymmetric monoallelic upregulation murine We categorize these into five classes: DNA elements, transcription factors, regulatory proteins, long RNAs, chromatin topological landscape surrounding Xist.

Language: Английский

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RNA in chromatin organization and nuclear architecture

Current Opinion in Genetics & Development, Journal Year: 2024, Volume and Issue: 86, P. 102176 - 102176

Published: March 14, 2024

Language: Английский

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