Shaping up genomes: Prokaryotic roots and eukaryotic diversification of SMC complexes

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 8, 2024

Summary Chromosome organization ensures accurate DNA replication, segregation, gene regulation and damage repair. Across the tree of life, protein assemblages termed Structural Maintenance Chromosomes (SMC) complexes determine chromosome organization. Eukaryotes usually have four SMC complex types (condensin I, condensin II, cohesin, SMC5/6), whereas prokaryotes mostly one. The expanded set is probably needed to accommodate considerably larger eukaryotic genomes. Despite their essential functions, exhibit notable variation among model organisms, suggesting underexplored diversity across eukaryotes. Here, we provide a thorough reconstruction evolution subunits accessory proteins We show that last common ancestor (LECA) had all complete complexes, supporting notion LECA was already sophisticated cell. At later timepoints, II lost at least thirty times, rendering it one most frequently cellular machineries. identify multiple components (e.g., Sororin, Securin, Nse5, Nse6) as much more ancient widespread than previously appreciated. Finally, traced prokaryotic origins these propose an duplicated in TACK Asgard archaea, archaeal inventory further through duplications, highlighting importance events emergence complexity. Altogether, our results address questions raise new ones about how affected genome organizations ancestral contemporary organisms.

Язык: Английский

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Cis-regulatory chromatin contacts form de novo in the absence of loop extrusion

Опубликована: Янв. 13, 2025

SUMMARY NIPBL promotes chromatin loop extrusion by the cohesin complex until it stalls at convergently oriented CTCF sites, leading to formation of structural loops. However, what extent contributes establishment vs maintenance cis -regulatory element (CRE) connectivity is poorly understood. Here, we explored de novo folding patterns mitosis-to-G1-phase transition upon acute loss. depletion primarily impaired cohesin-mediated loops with dependence being proportional length. In contrast, majority CRE were established independently regardless slowed re-formation weak enhancers. Transcription genes NIPBL-independent anchors was activated normally in absence NIPBL. sum, most regulatory contacts and gene transcription following mitotic exit independent extrusion.

Язык: Английский

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Regulation of CTCF loop formation during pancreatic cell differentiation

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Окт. 9, 2023

Abstract Transcription reprogramming during cell differentiation involves targeting enhancers to genes responsible for establishment of fates. To understand the contribution CTCF-mediated chromatin organization lineage commitment, we analyzed 3D architecture human embryonic stem cells into pancreatic islet organoids. We find that CTCF loops are formed and disassembled at different stages process by either recruitment new anchor sites or use pre-existing not previously involved in loop formation. Recruitment genome demethylation H3K9me3 H3K9me2, DNA, pioneer factors, positioning nucleosomes flanking sites. Existing formation become functional anchors via cohesin loading containing NIPBL YY1 between anchors. In both cases, leads strengthening enhancer promoter interactions increased transcription adjacent These results suggest an important role controlling gene expression differentiation.

Язык: Английский

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STAG2: Computational Analysis of Missense Variants Involved in Disease

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(2), С. 1280 - 1280

Опубликована: Янв. 20, 2024

The human STAG2 protein is an essential component of the cohesin complex involved in cellular processes gene expression, DNA repair, and genomic integrity. Somatic mutations sequence have been associated with various types cancer, while congenital variants linked to developmental disorders such as Mullegama–Klein–Martinez syndrome, X-linked holoprosencephaly-13, Cornelia de Lange syndrome. In complex, direct interaction NIPBL, RAD21, CTCF proteins has described. function within still unknown, but it related its binding capacity modulated by other three proteins. Every missense variant described for located regions one these interactions. present work, we model structure 12 STAG2, well two NIPBl RAD21 at zone, then analyze their behavior through molecular dynamic simulations, comparing them same simulation wild-type protein. This will allow effects be rationalized atomic level provide clues how functions complex.

Язык: Английский

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Analysis of long-range chromatin contacts, compartments and looping between mouse embryonic stem cells, lens epithelium and lens fibers

Epigenetics & Chromatin, Год журнала: 2024, Номер 17(1)

Опубликована: Апрель 20, 2024

Nuclear organization of interphase chromosomes involves individual chromosome territories, "open" and "closed" chromatin compartments, topologically associated domains (TADs) loops. The DNA- RNA-binding transcription factor CTCF together with the cohesin complex serve as major organizers architecture. Cellular differentiation is driven by temporally spatially coordinated gene expression that requires changes loci various complexities. Lens represents an advantageous system to probe transcriptional mechanisms underlying tissue-specific including high outputs crystallin genes until mature lens fiber cells degrade their nuclei. Chromatin between mouse embryonic stem (ES) cells, newborn (P0.5) epithelium were analyzed using Hi-C. Localization in both chromatins was determined ChIP-seq compared ES cells. Quantitative analyses show differences number size TADs loop these three cell types. In depth similarities samples exemplified overlaps compartments A B. epithelium-specific peaks are found mostly methylated genomic regions while fiber-specific shared occur within unmethylated DNA regions. Major loops illustrated at ~ 500 kb Pax6 locus, encoding critical regulatory a larger 15 Mb WAGR containing other linked human congenital diseases. Hi-C data (TADs loops) ATAC-seq, CTCF, H3K27ac, H3K27me3 ENCODE cis-regulatory sites shown detail for Pax6, Sox1 Hif1a loci, multiple important required morphogenesis. majority marked unexpectedly CTCF-binding across transcribed Our study has generated first on 3-dimensional (3D) nuclear fibers directly These findings generate novel insights into lens-specific control, open new research avenues condensates enable studies non-coding genetic variants cataract ocular abnormalities.

Язык: Английский

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DCAF15 control of cohesin dynamics sustains acute myeloid leukemia

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июль 3, 2024

The CRL4-DCAF15 E3 ubiquitin ligase complex is targeted by the aryl-sulfonamide molecular glues, leading to neo-substrate recruitment, ubiquitination, and proteasomal degradation. However, physiological function of DCAF15 remains unknown. Using a domain-focused genetic screening approach, we reveal as an acute myeloid leukemia (AML)-biased dependency. Loss results in suppression AML through compromised replication fork integrity consequent accumulation DNA damage. Accordingly, loss sensitizes stress-inducing therapeutics. Mechanistically, discover that directly interacts with SMC1A protein cohesin destabilizes regulatory factors PDS5A CDCA5. CDCA5 removal precludes acetylation on chromatin, resulting uncontrolled chromatin loop extrusion, defective replication, apoptosis. Collectively, our findings uncover endogenous, cell autonomous sustaining proliferation post-translational control dynamics.

Язык: Английский

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Co-essentiality analysis identifies PRR12 as a cohesin interacting protein and contributor to genomic integrity

Developmental Cell, Год журнала: 2024, Номер unknown

Опубликована: Дек. 1, 2024

Язык: Английский

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Increasingly efficient chromatin binding of cohesin and CTCF supports chromatin architecture formation during zebrafish embryogenesis

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 20, 2025

The three-dimensional folding of chromosomes is essential for nuclear functions such as DNA replication and gene regulation. emergence chromatin architecture thus an important process during embryogenesis. To shed light on the molecular kinetic underpinnings formation, we characterized biophysical properties cohesin CTCF binding to their changes upon cofactor depletion using single-molecule imaging in live developing zebrafish embryos. We found that chromatin-bound fractions both increased significantly between 1000-cell shield stages, which could explain through association dissociation rates. Moreover, increasing restricted motion, potentially via loop extrusion, showed distinct stage-dependent distribution. Polymer simulations with experimentally derived parameters recapitulated observed gradual architecture. Our findings reveal kinetics underlying formation

Язык: Английский

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Meiosis-specific distal cohesion site decoupled from the kinetochore

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 3, 2025

Abstract Primary constriction of the M-phase chromosome serves as a marker for kinetochore position. Underlying this observation is concept that spatially linked with pericentromere where sister-chromatids are cohered. Here, we find an unconventional chromatid-cohesion pattern in Peromyscus oocytes, sister chromatids cohered at end, separated from kinetochore. This distal locus enriches cohesin protectors specifically during meiosis, and chromosomes additional cohesion site exhibit enhanced protection anaphase I compared to those without it, implying adaptive evolution ensure meiosis. The corresponds centromeric satellite block, located far block building Analyses on three species reveal internal consistently assembles mitosis whereas selectively meiosis promote cohesion. Our study demonstrates regulation flexible, controlling segregation cell-type dependent manner.

Язык: Английский

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STAG1 Disease, Central Precocious Puberty, and Bone Fragility—A Case Report

Diagnostics, Год журнала: 2025, Номер 15(9), С. 1076 - 1076

Опубликована: Апрель 24, 2025

Background: Previously reported STAG1 gene-related cohesinopathies describe a range of clinical features, typically including intellectual disability (ID), facial dysmorphisms, and limb anomalies. Case presentation: We present the case an 8-year-old girl with main findings ID, central precocious puberty (CPP), bone fragility. Panel genetic testing revealed pathogenic variant, NM_005862.3:c.2116del p.(Asp706Ilefs*15), which can only partially explain phenotype. Reports STAG1-related cohesinopathies, ours, have consistently described developmental disabilities. In our case, etiology CPP fragility remains unexplained. discuss challenges limitations current molecular tools in assessing cases overlapping, apparently unlinked phenotypes, while speculating whether common occurrence could be explained by instead. Conclusions: The spectrum is still poorly understood. Complex phenotypes unrelated features warrant further careful investigation illustrate diagnosis.

Язык: Английский

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