Cohesin regulation and roles in chromosome structure and function

Current Opinion in Genetics & Development, Journal Year: 2024, Volume and Issue: 85, P. 102159 - 102159

Published: Feb. 20, 2024

Chromosome structure regulates DNA-templated processes such as transcription of genes. Dynamic changes to chromosome occur during development and in disease contexts. The cohesin complex is a molecular motor that by generating DNA loops bring two distal genomic sites into close spatial proximity. There are many open questions regarding the formation dissolution loops, well role(s) regulating interphase genome. This review focuses on recent discoveries provide insights role gene disease.

Language: Английский

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LncRNA CARMN inhibits abdominal aortic aneurysm formation and vascular smooth muscle cell phenotypic transformation by interacting with SRF

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: April 10, 2024

Abstract Phenotypic transformation of vascular smooth muscle cells (VSMCs) plays a crucial role in abdominal aortic aneurysm (AAA) formation. CARMN, highly conserved, VSMC-enriched long noncoding RNA (lncRNA), is integral orchestrating various pathologies by modulating the phenotypic dynamics VSMCs. The influence CARMN on AAA formation, particularly its mechanisms, remains enigmatic. Our research, employing single-cell and bulk sequencing, has uncovered significant suppression specimens, which correlates strongly with contractile function This reduced expression was consistent both 7- 14-day porcine pancreatic elastase (PPE)-induced mouse models human clinical cases. Functional analyses disclosed that diminution exacerbated PPE-precipitated whereas augmentation conferred protection against such Mechanistically, we found CARMN's capacity to bind SRF, thereby amplifying driving transcription VSMC marker genes. In addition, our findings indicate an enhancement CAMRN transcription, facilitated binding NRF2 promoter region. study indicated protective preventing formation restrains through interaction SRF. Additionally, observed augmented These suggest potential as viable therapeutic target treatment AAA. Graphical abstract

Language: Английский

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Repression of CADM1 transcription by HPV type 18 is mediated by three-dimensional rearrangement of promoter-enhancer interactions

PLoS Pathogens, Journal Year: 2025, Volume and Issue: 21(1), P. e1012506 - e1012506

Published: Jan. 27, 2025

Upon infection, human papillomavirus (HPV) manipulates host cell gene expression to create an environment that is supportive of a productive and persistent infection. The virus-induced changes the cell’s transcriptome are thought contribute carcinogenesis. Here, we show by RNA-sequencing oncogenic HPV18 episome replication in primary foreskin keratinocytes (HFKs) drives transcriptional consistent between multiple HFK donors. We have previously shown recruits protein CTCF viral episomes control differentiation-dependent programme. Since important regulator transcription via coordination epigenetic boundaries long-range chromosomal interactions, hypothesised may also manipulate reprogramming. Analysis binding genome ChIP-Seq revealed while total number sites not altered virus, there sub-set either enriched or depleted CTCF. Many these clustered within regulatory elements differentially expressed genes, including tumour suppressor adhesion molecule 1 ( CADM1 ), which supresses epithelial growth invasion. establishment results reduced at promoter upstream enhancer. Loss coincident with repression CADM1, absence CpG hypermethylation, adjacent genes ZBTB16 activated. These data indicate locus subject topological rearrangement following establishment. tested this hypothesis using 4C-Seq (circular chromosome confirmation capture-sequencing) causes loss interactions start site promoter-enhancer drive reprogramming HPV-induced disease progression.

Language: Английский

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

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

Published: Feb. 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

Language: Английский

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N⁶-Methyladenosine mRNA Modification: From Modification Site Selectivity to Neurological Functions

Accounts of Chemical Research, Journal Year: 2023, Volume and Issue: 56(21), P. 2992 - 2999

Published: Oct. 17, 2023

The development of various chemical methods has enabled scientists to decipher the distribution features and biological functions RNA modifications in past decade. In addition modifying noncoding RNAs such as tRNAs rRNAs, N6-methyladenosine (m6A) been proven be most abundant internal modification on mRNAs eukaryotic cells is also widely studied mRNA date. Extensive studies have repeatedly demonstrated important m6A conditions, ranging from embryonic organ adult function pathogenesis. Unlike DNA methylation which relatively stable, reversible highly dynamic easily influenced by or external factors, cell type, developmental stage, nutrient supply, circadian rhythm, environmental stresses.In this Account, we review our previous findings site selectivity mechanisms regulating formation, well physiological roles cerebellum long-term memory consolidation. initial efforts profile types mouse human cells, surprisingly found that sequence motifs surrounding sites were often complementary with seed sequences miRNAs. By manipulating abundance miRNA biogenesis enzyme Dicer individual miRNAs mutating sequences, able reveal a new role nucleus localized miRNAs, guide methyltransferase METTL3 bind promote formation. As result, partially answered question why only small proportion within an could at certain time point. We further explored brain functions. had severe defects when Mettl3 was knocked out developing revealed underlying attributed aberrant splicing enhanced apoptosis under deficit conditions. On other hand, knocking postnatal hippocampus did not cause morphological but impaired efficacy Under learning stimuli, formation detected transcripts encoding proteins related dendrite growth, synapse Loss these would result translation deficiency reduced protein production, particularly early response genes, therefore compromise Interestingly, excessive training sessions increased intensity overcome defects, likely due longer turnover cycle cumulative throughout process. revealing work effective method for studying efficacy. lack appropriate model long-lasting problem field neural science, hippocampus-specific knockout utilized study questions

Language: Английский

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Ionizing radiation induces vascular smooth muscle cell senescence through activating NF-κB/CTCF/p16 pathway

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2023, Volume and Issue: 1870(3), P. 166994 - 166994

Published: Dec. 21, 2023

Language: Английский

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5-Hydroxymethylcytosine in circulating cell-free DNA as a potential diagnostic biomarker for SLE

Lupus Science & Medicine, Journal Year: 2024, Volume and Issue: 11(2), P. e001286 - e001286

Published: Oct. 1, 2024

SLE is a complex autoimmune disease with heterogeneous manifestations and unpredictable outcomes. Early diagnosis challenging due to non-specific symptoms, current treatments only manage symptoms. Epigenetic alternations, including 5-Hydroxymethylome (5hmC) modifications, are important contributors pathogenesis. However, the 5hmC modification status in circulating cell-free DNA (cfDNA) of patients remains largely unexplored. We investigated distribution cfDNA healthy controls (HCs), explored its potential as an marker.

Language: Английский

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The chromatin conformation landscape of Alzheimer’s disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 13, 2024

ABSTRACT We have been investigating epigenetic alterations in the brain during human aging and Alzheimer’s disease (AD), evidence for histone acetylation both protecting epigenome driving AD. Here we extend our studies to chromatin architecture via looping studies, with binding of key proteins required looping: CTCF RAD21. detected changes RAD21 levels localization, finding major AD compared fewer healthy aging. In study 3D genome conformation changes, identified stable topological associating domains (TADs) Old AD; contrast, AD, there is loss interaction at genomic sites/loops within TADs, likely reflecting CTCF. genes potential transcription factor loops that are lost addition, found enrichment peak losses eQTLs, suggesting architectural dysfunction has a role Alzheimer’s. Functional experiments lowering homologues several Drosophila model Aβ42 toxicity exacerbate neurodegeneration. Taken together, these data indicate functional protections occur normal

Language: Английский

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Loopy virus or controlled contortionist? 3D regulation of HCMV gene expression by CTCF-driven chromatin interactions

Journal of Virology, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 30, 2024

ABSTRACT Three-dimensional chromatin control of eukaryotic transcription is pivotal for regulating gene expression. This additional layer epigenetic regulation also utilized by DNA viruses, including herpesviruses. Dynamic, spatial genomic organization often involves looping anchored host-encoded CCCTC-binding factor (CTCF) and other factors, which crosstalk between promoters enhancers. Herein, we review the contribution CTCF-mediated in during herpesvirus infection, with a specific focus on betaherpesvirus, human cytomegalovirus (HCMV).

Language: Английский

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Repression of CADM1 transcription by HPV type 18 is mediated by three-dimensional rearrangement of promoter-enhancer interactions

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 16, 2024

ABSTRACT Upon infection, human papillomavirus (HPV) manipulates host cell gene expression to create an environment that is supportive of a productive and persistent infection. The virus-induced changes the cell’s transcriptome are thought contribute carcinogenesis. Here, we show by RNA-sequencing oncogenic HPV18 episome replication in primary foreskin keratinocytes (HFKs) drives transcriptional consistent between multiple HFK donors. We have previously shown HFKs results post-transcriptional stabilisation chromatin insulation protein CTCF. Since CTCF important regulator transcription via coordination epigenetic boundaries long-range chromosomal interactions, hypothesised HPV18-induced may reprogramming. Analysis binding genome ChIP-Seq revealed while total number sites not altered virus, there sub-set either enriched or depleted Many these clustered within regulatory elements differentially expressed genes, including tumour suppressor adhesion molecule 1 ( CADM1 ), which supresses epithelial growth invasion. establishment reduced at promoter upstream enhancer. Loss coincident with repression CADM1, absence CpG hypermethylation, adjacent genes ZBTB16 activated. These data indicate locus subject topological rearrangement following establishment. tested this hypothesis using 4C-Seq (circular chromosome confirmation capture-sequencing) causes loss interactions start site promoter-enhancer drive reprogramming HPV-induced disease progression. AUTHOR SUMMARY Infection HPV cause numerous cancer types, generally arise after alters profile infected cells facilitate virus persistence. Multiple mechanisms been suggested. infection induces specific genomic loci altering CTCF, architecture. cluster on 11 disruption resulting . Our early event HPV-driven disease, preceding hypermethylation frequently observed cancers, demonstrating novel mechanism

Language: Английский

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