Genome-wide maps of nucleolus interactions reveal distinct layers of repressive chromatin domains

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Март 18, 2022

Abstract Eukaryotic chromosomes are folded into hierarchical domains, forming functional compartments. Nuclear periphery and nucleolus two nuclear landmarks contributing to repressive chromosome architecture. However, while the role of lamina (NL) in genome organization has been well documented, function remains under-investigated due lack methods for identification nucleolar associated domains (NADs). Here we have established DamID- HiC-based methodologies generate accurate genome-wide maps NADs embryonic stem cells (ESCs) neural progenitor (NPCs), revealing layers compartmentalization with distinct, chromatin states based on interaction nucleolus, NL, or both. show higher H3K9me2 lower H3K27me3 content than regions exclusively interacting NL. Upon ESC differentiation NPCs, around acquire a more compact, rigid architecture genes moving away from nucleoli becoming unlocked later activation. Further, histone modifications strength within A B compartments LADs ESCs set choice associate NL upon dissociation their respective during differentiation. The here developed will make possible include contribution space diverse biological systems.

Язык: Английский

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Endogenous Double-Stranded RNA

Non-Coding RNA, Год журнала: 2021, Номер 7(1), С. 15 - 15

Опубликована: Фев. 19, 2021

The birth of long non-coding RNAs (lncRNAs) is closely associated with the presence and activation repetitive elements in genome. transcription endogenous retroviruses as well short interspersed not only essential for evolving lncRNAs but also a significant source double-stranded RNA (dsRNA). From an lncRNA-centric point view, latter minor bother context entire cell; however, dsRNA threat. A viral infection cytoplasmic dsRNA, hybrids differ from by 5′ cap structure. Hence, multi-layered defense network place to protect cells infections tolerates structures. first line established compartmentalization; whereas found predominantly confined nucleus mitochondria, exogenous reaches cytoplasm. Here, various sensor proteins recognize features including phosphate group or particular length specific nucleotide sequences. sensors trigger cellular stress pathways innate immunity via interferon signaling induce apoptosis caspase activation. Because its central role recognition immune activation, sensing implicated autoimmune diseases used treat cancer.

Язык: Английский

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Nucleolar-based Dux repression is essential for embryonic two-cell stage exit

Genes & Development, Год журнала: 2022, Номер 36(5-6), С. 331 - 347

Опубликована: Март 1, 2022

Upon fertilization, the mammalian embryo must switch from dependence on maternal transcripts to transcribing its own genome, and in mice this involves transient up-regulation of MERVL transposons MERVL-driven genes at two-cell stage. The mechanisms requirement for (2C) gene are poorly understood. Moreover, transcriptional program be rapidly shut off allow exit developmental progression. Here, we report that robust ribosomal RNA (rRNA) synthesis nucleolar maturation essential 2C state. 2C-like cells embryos show similar immature nucleoli with altered structure reduced rRNA output. We reveal disruption via blocking polymerase I activity or preventing phase separation enhances conversion a state embryonic stem (ESCs) by detachment activator Dux surface. In embryos, prevents proper silencing leads two- four-cell arrest. Our findings an intriguing link between synthesis, maturation, repression during early development.

Язык: Английский

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Comparative 3D genome architecture in vertebrates

BMC Biology, Год журнала: 2022, Номер 20(1)

Опубликована: Май 6, 2022

Abstract Background The three-dimensional (3D) architecture of the genome has a highly ordered and hierarchical nature, which influences regulation essential nuclear processes at basis gene expression, such as transcription. While organization heterochromatin euchromatin can underlie differences in expression that determine evolutionary among species, way 3D is affected by forces within major lineages remains unclear. Here, we report comprehensive comparison genomes, using high resolution Hi-C data fibroblast cells fish, chickens, 10 mammalian species. Results This analysis shows correlation between size chromosome length affects territory (CT) upper hierarchy architecture, whereas lower features, including local transcriptional availability DNA, are selected through evolution vertebrates. Furthermore, conservation topologically associating domains (TADs) appears strongly associated with modularity profiles across Additionally, LINE SINE transposable elements likely contribute to organization, respectively, during architecture. Conclusions Our uncovers organizational features appear functional genes These findings guide ongoing investigations extending our understanding mechanisms shaping

Язык: Английский

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NR5A2 connects zygotic genome activation to the first lineage segregation in totipotent embryos

Cell Research, Год журнала: 2023, Номер 33(12), С. 952 - 966

Опубликована: Ноя. 7, 2023

Abstract Zygotic genome activation (ZGA) marks the beginning of embryonic program for a totipotent embryo, which gives rise to inner cell mass (ICM) where pluripotent epiblast arises, and extraembryonic trophectoderm. However, how ZGA is connected first lineage segregation in mammalian embryos remains elusive. Here, we investigated role nuclear receptor (NR) transcription factors (TFs), whose motifs are highly enriched accessible from 2-cell (2C) 8-cell (8C) stages mouse embryos. We found that NR5A2, an NR TF strongly induced upon ZGA, was required this connection. Upon Nr5a2 knockdown or knockout, developed beyond 2C normally with zygotic largely activated. 4–8C-specific gene substantially impaired -deficient subsequently arrested at morula stage. Genome-wide chromatin binding analysis showed NR5A2-bound cis -regulatory elements both 8C B1 its motif embedded. NR5A2 not global opening sites but essential 8C-specific sites. These 8C-specific, 2C-specific, near genes involved blastocyst stem regulation, often bound by master pluripotency TFs blastocysts cells (ESCs). Importantly, regulated key Nanog Pou5f1/Oct4 , primitive endoderm regulatory including Gata6 among many early ICM genes, as well trophectoderm Tead4 Gata3 By contrast, NANOG, SOX2, OCT4 targeted late ESCs. Taken together, these data identify regulator bridges during development.

Язык: Английский

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Nucleosomes in mammalian sperm: conveying paternal epigenetic inheritance or subject to reprogramming between generations?

Current Opinion in Genetics & Development, Год журнала: 2023, Номер 79, С. 102034 - 102034

Опубликована: Март 7, 2023

The genome of mammalian sperm is largely packaged by sperm-specific proteins termed protamines. presence some residual nucleosomes has, however, emerged as a potential source paternal epigenetic inheritance between generations. Sperm bear important regulatory histone marks and locate at gene-regulatory regions, functional elements, intergenic regions. It unclear whether are retained specific genomic locations in deterministic manner or randomly preserved due to inefficient exchange histones Recent studies indicate heterogeneity chromatin packaging within populations an extensive reprogramming post fertilization. Obtaining single-sperm nucleosome distributions fundamental estimating the sperm-borne instructing embryonic development transmission acquired phenotypes.

Язык: Английский

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CDCA7-associated global aberrant DNA hypomethylation translates to localized, tissue-specific transcriptional responses

Science Advances, Год журнала: 2024, Номер 10(6)

Опубликована: Фев. 9, 2024

Disruption of cell division cycle associated 7 (CDCA7) has been linked to aberrant DNA hypomethylation, but the impact methylation loss on transcription not investigated. Here, we show that CDCA7 is critical for maintaining global levels across multiple tissues in vivo. A pathogenic

Язык: Английский

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Chromosome-scale genome assembly reveals how repeat elements shape non-coding RNA landscapes active during newt limb regeneration

Cell Genomics, Год журнала: 2025, Номер unknown, С. 100761 - 100761

Опубликована: Янв. 1, 2025

Язык: Английский

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rRNA biogenesis regulates mouse 2C-like state by 3D structure reorganization of peri-nucleolar heterochromatin

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Ноя. 9, 2021

Abstract The nucleolus is the organelle for ribosome biogenesis and sensing various types of stress. However, its role in regulating stem cell fate remains unclear. Here, we present evidence that nucleolar stress induced by interfering rRNA can drive 2-cell stage embryo-like (2C-like) program induce an expanded 2C-like population mouse embryonic (mES) cells. Mechanistically, integrity maintains normal liquid-liquid phase separation (LLPS) formation peri-nucleolar heterochromatin (PNH). Upon defects biogenesis, natural state LLPS disrupted, causing dissociation NCL/TRIM28 complex from PNH changes epigenetic reorganization 3D structure PNH, which leads to release Dux, a 2C transcription factor, activate program. Correspondingly, embryos with defect are unable develop (2C) 4-cell embryos, delayed repression 2C/ERV genes transcriptome skewed toward earlier cleavage embryo signatures. Our results highlight rRNA-mediated reshaping compartment regulates transition mES cells cells, critical regulator during murine pre-implantation development.

Язык: Английский

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Transposable elements as new players in neurodegenerative diseases

FEBS Letters, Год журнала: 2021, Номер 595(22), С. 2733 - 2755

Опубликована: Окт. 9, 2021

Neurodegenerative diseases (NDs), including the most prevalent Alzheimer's disease and Parkinson disease, share common pathological features. Despite decades of gene-centric approaches, molecular mechanisms underlying these remain widely elusive. In recent years, transposable elements (TEs), long considered 'junk' DNA, have gained growing interest as pathogenic players in NDs. Age is major risk factor for NDs, several repressive TEs, such heterochromatinization, fail with age. Indeed, heterochromatin relaxation leading to TE derepression has been reported various models neurodegeneration There also evidence that certain proteins involved NDs (e.g., tau, TDP-43) may control expression TEs. The deleterious consequences activation are not well known but they could include DNA damage genomic instability, altered host gene expression, and/or neuroinflammation, which hallmarks aging. TEs might thus represent an overlooked culprit both brain aging neurodegeneration. Certain effects be prevented by inhibiting their activity, pointing novel targets neuroprotection.

Язык: Английский

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