Beyond the Synapse: FMR1 and FMRP Molecular Mechanisms in the Nucleus DOI Open Access
Nicole Hansen, Anna Dischler, Caroline Dias

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 26(1), P. 214 - 214

Published: Dec. 30, 2024

FMR1 (Fragile X messenger ribonucleoprotein 1), located on the X-chromosome, encodes multi-functional protein (FMRP), critical to brain development and function. Trinucleotide CGG repeat expansions at this locus cause a range of neurological disorders, collectively referred as Fragile X-related conditions. The most well-known these is syndrome, neurodevelopmental disorder associated with syndromic facial features, autism, intellectual disabilities, seizures. However, different sizes also confer risk neuropsychiatric neurodegenerative disorders throughout lifespan, through distinct molecular mechanisms. Although syndrome downstream synaptic deficits neuronal hyperexcitability, work in past decade has demonstrated that both causative trinucleotide expansion FMRP itself play important roles nuclear function regulation, including non-canonical nucleic acid structure formation chromatin dynamics. These effects are cellular pathophysiology, although full extent their contribution clinical phenotypes only just emerging. Here, we present focused review some consequences FMR1/FMRP dysregulation, parallels other ranging from studies model systems human cells tissues.

Language: Английский

Roles of chromatin and genome instability in cellular senescence and their relevance to ageing and related diseases DOI
Zeming Wu, Jing Qu, Guang‐Hui Liu

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(12), P. 979 - 1000

Published: Oct. 3, 2024

Language: Английский

Citations

10
Spatial orchestration of the genome: topological reorganisation during X-chromosome inactivation DOI Creative Commons
Alexandra Martitz, Edda G. Schulz

Current Opinion in Genetics & Development, Journal Year: 2024, Volume and Issue: 86, P. 102198 - 102198

Published: April 24, 2024

Genomes are organised through hierarchical structures, ranging from local kilobase-scale cis-regulatory contacts to large chromosome territories. Most notably, (sub)-compartments partition chromosomes according transcriptional activity, while topologically associating domains (TADs) define landscapes. The inactive X in mammals has provided unique insights into the regulation and function of three-dimensional (3D) genome. Concurrent with silencing majority genes major alterations its chromatin state, undergoes profound spatial rearrangements at multiple scales. These include emergence megadomains, compartment structure loss TADs. Moreover, Xist locus, which orchestrates X-chromosome inactivation, key regulatory domains. This review provides an overview recent control these structural contextualises them within a broader understanding 3D genome organisation.

Language: Английский

Citations

5
C9orf72 expansion creates the unstable folate-sensitive fragile site FRA9A DOI Creative Commons

Mila Mirceta,

Monika H.M. Schmidt,

Natalie Shum

et al.

Deleted Journal, Journal Year: 2024, Volume and Issue: 1(4)

Published: Oct. 1, 2024

Abstract The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions (C9orf72Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia autoimmune disorders. C9orf72Exp patients display hyperactive cGAS-STING-linked immune DNA damage responses, but source of immunostimulatory or damaged unknown. Here, we show in pre-symptomatic sclerosis-frontotemporal patient cells brains cause folate-sensitive chromosomal fragile site, FRA9A. FRA9A centers on >33 kb as highly compacted chromatin embedded an 8.2 Mb fragility zone spanning 9p21, encompassing 46 genes, making one largest sites. instability, heightened global- Chr9p-enriched sister-chromatid exchanges, truncated-Chr9s, acentric-Chr9s Chr9-containing micronuclei, providing endogenous sources DNA. Cells from contained a rearranged FRA9A-expressing Chr9 Chr9-wide dysregulated expression. Somatic repeat instability sensitive folate deficiency. Age-dependent can be transferred CNS peripheral tissues transgenic mice, implicating source. Our results highlight unappreciated effects that trigger vitamin-sensitive chromosome fragility, adding structural variations disease-enriched 9p21 likely elsewhere.

Language: Английский

Citations

5
Mosaicism in Short Tandem Repeat Disorders: A Clinical Perspective DOI Open Access

Rose M. Doss,

Susana Lopez-Ignacio,

Anna Dischler

et al.

Genes, Journal Year: 2025, Volume and Issue: 16(2), P. 216 - 216

Published: Feb. 13, 2025

Fragile X, Huntington disease, and myotonic dystrophy type 1 are prototypical examples of human disorders caused by short tandem repeat variation, repetitive nucleotide stretches that highly mutable both in the germline somatic tissue. As repeats unstable, they can expand, contract, acquire lose epigenetic marks This means within an individual, genotype state at these loci vary considerably from cell to cell. mosaicism may play a key role clinical pathogenesis, yet, our understanding driving phenotypes is only just emerging. review focuses on three relatively well-studied where, given advent new technologies bioinformatic approaches, critical for coming into focus with respect cellular physiology phenotypes.

Language: Английский

Citations

0
FISHnet: detecting chromatin domains in single-cell sequential Oligopaints imaging data DOI Creative Commons
Rohan Patel, Kenneth Pham, Harshini Chandrashekar

et al.

Nature Methods, Journal Year: 2025, Volume and Issue: unknown

Published: May 12, 2025

Language: Английский

Citations

0
The role of epigenetics in women’s reproductive health: the impact of environmental factors DOI Creative Commons

Xinru Yu,

Jiawei Xu,

Bihan Song

et al.

Frontiers in Endocrinology, Journal Year: 2024, Volume and Issue: 15

Published: Sept. 13, 2024

This paper explores the significant role of epigenetics in women's reproductive health, focusing on impact environmental factors. It highlights crucial link between epigenetic modifications-such as DNA methylation and histones post-translational modifications-and health issues, including infertility pregnancy complications. The reviews influence pollutants like PM2.5, heavy metals, endocrine disruptors gene expression through mechanisms, emphasizing need for understanding how dietary, lifestyle choices, exposure to chemicals affect health. Future research directions include deeper investigation into female leveraging editing mitigate changes improving IVF success rates managing disorders.

Language: Английский

Citations

3
C9orf72expansion creates the unstable folate-sensitive fragile site FRA9A DOI Open Access

Mila Mirceta,

Monika H.M. Schmidt,

Natalie Shum

et al.

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

Published: Oct. 29, 2024

Abstract The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions ( Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia autoimmune disorders. Exp patients display hyperactive cGAS-STING-linked immune DNA damage responses, but source of immuno-stimulatory or damaged unknown. Here, we show in pre-symptomatic ALS-FTD patient cells brains cause folate-sensitive chromosomal fragile site, FRA9A. FRA9A centers on >33kb as highly-compacted chromatin embedded an 8.2Mb fragility zone spanning 9p21, encompassing 46 genes, making one largest sites. instability, heightened global- Chr9p-enriched sister-chromatid exchanges, truncated-Chr9s, acentric-Chr9s Chr9-containing micronuclei, providing endogenous sources immunostimulatory DNA. Cells from contained highly-rearranged FRA9A-expressing Chr9 Chr9-wide dysregulated expression. Somatic repeat instability sensitive folate-deficiency. Age-dependent fragility, can be transferred CNS peripheral tissues transgenic mice, implicating source. Our results highlight unappreciated effects that trigger vitamin-sensitive chromosome adding structural variations disease-enriched 9p21 likely elsewhere.

Language: Английский

Citations

1
BREACHing new grounds in fragile X syndrome: Trinucleotide expansion linked to genome-wide heterochromatin domains and genome misfolding DOI Creative Commons
Edda G. Schulz

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(3), P. 413 - 414

Published: Feb. 1, 2024

Language: Английский

Citations

0
3D epigenomics and 3D epigenopathies DOI Creative Commons

Kyunghwan Lee,

J. W. Kim,

Ji Hun Kim

et al.

BMB Reports, Journal Year: 2024, Volume and Issue: 57(5), P. 216 - 231

Published: April 12, 2024

Mammalian genomes are intricately compacted to form sophisticated 3-dimensional structures within the tiny nucleus, so called 3D genome folding. Despite their shapes reminiscent of an entangled yarn, rapid development molecular and next-generation sequencing technologies (NGS) has revealed that mammalian highly organized in a hierarchical order delicately affects transcription activities. An increasing amount evidence suggests folding is implicated diseases, giving us clue on how identify novel therapeutic approaches. In this review, we will study what means epigenetics, types there are, they formed, have developed explore them. We also discuss pathological implications Finally, leverage engineering for future studies. [BMB Reports 2024; 57(5): 216-231].

Language: Английский

Citations

0
MASTR-seq: Multiplexed Analysis of Short Tandem Repeats with sequencing DOI Creative Commons
Chuanbin Su, Keerthivasan Raanin Chandradoss, Thomas Malachowski

et al.

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

Published: May 2, 2024

More than 60 human disorders have been linked to unstable expansion of short tandem repeat (STR) tracts. STR length and the extent DNA methylation is disease pathology can be mosaic in a cell type-specific manner several disorders. Mosaic phenomenon difficult study date due technical bias intrinsic sequences need for multi-modal measurements at single-allele resolution. Nanopore long-read sequencing accurately measures same single molecule but cost prohibitive studies assessing target locus across multiple experimental conditions or patient samples. Here, we describe MASTR-seq, M ultiplexed A nalysis S hort T andem R epeats, cost-effective, high-throughput, accurate, genotype MASTR-seq couples sequencing, Cas9-mediated enrichment, PCR-free multiplexed barcoding achieve >ten-fold increase on-target read mapping 8-12 pooled samples MinION flow cell. We provide detailed protocol computational tools present evidence that quantifies tract status CGG CAG loci normal-length mutation-length lines. The takes approximately eight days experiments one additional day data processing analyses.

Language: Английский

Citations

0