Transposable elements in mammalian chromatin organization

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 24(10), P. 712 - 723

Published: June 7, 2023

Language: Английский

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Epigenetic regulatory layers in the 3D nucleus

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(3), P. 415 - 428

Published: Jan. 18, 2024

Nearly 7 decades have elapsed since Francis Crick introduced the central dogma of molecular biology, as part his ideas on protein synthesis, setting fundamental rules sequence information transfer from DNA to RNAs and proteins. We learned that gene expression is finely tuned in time space, due activities proteins regulatory elements, through cell-type-specific three-dimensional conformations genome. Here, we review major advances genome biology discuss a set regulation highlight how various biomolecular assemblies lead formation structural features within nucleus, with roles transcriptional control. conclude by suggesting further developments will help capture complex, dynamic, often spatially restricted events govern mammalian cells.

Language: Английский

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Polygenic burden of short tandem repeat expansions promotes risk for Alzheimer’s disease

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

Published: Jan. 28, 2025

Studies of the genetics Alzheimer's disease (AD) have largely focused on single nucleotide variants and short insertions/deletions. However, most heritability has yet to be uncovered, suggesting that there is substantial genetic risk conferred by other forms variation. There are over one million tandem repeats (STRs) in genome, their link AD not been assessed. As pathogenic expansions STR cause 30 neurologic diseases, it important ascertain whether STRs may also implicated risk. Here, we genotype 312,731 polymorphic tracts genome-wide using PCR-free whole genome sequencing data from 2981 individuals (1489 case 1492 control individuals). We implement an approach identify as with tract lengths outliers population. then test for differences aggregate burden versus individuals. patients harbor a 1.19-fold increase compared healthy elderly controls (p = 8.27×10-3, two-sided Mann-Whitney test). Individuals carrying >30 3.69-fold higher odds having more severe neuropathology. highly enriched within active promoters post-mortem hippocampal brain tissues particularly SINE-VNTR-Alu (SVA) retrotransposons. Together, these results demonstrate expanded promoter regions associate AD. The authors explore how DNA sequences affect disease. They find who carry high than three-fold increased

Language: Английский

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Diverse heterochromatin states restricting cell identity and reprogramming

Trends in Biochemical Sciences, Journal Year: 2023, Volume and Issue: 48(6), P. 513 - 526

Published: March 27, 2023

Language: Английский

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Transposable Elements Co-Option in Genome Evolution and Gene Regulation

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2610 - 2610

Published: Jan. 30, 2023

The genome is no longer deemed as a fixed and inert item but rather moldable matter that continuously evolving adapting. Within this frame, Transposable Elements (TEs), ubiquitous, mobile, repetitive elements, are considered an alive portion of the genomes to date, whose functions, although long “dark”, now coming light. Here we will review that, besides detrimental effects TE mobilization can induce, TEs have shaped in their current form, promoting sizing, genomic rearrangements shuffling DNA sequences. Although mostly represented by evolutionarily old, short, degenerated, sedentary fossils, they been thoroughly co-opted hosts prolific original source regulatory instruments for control gene transcription organization nuclear space. For these reasons, deregulation expression and/or activity implicated onset progression several diseases. It likely just revealed outermost layers functions. Further studies on required unlock novel functions could also be exploited diagnostic therapeutic approaches.

Language: Английский

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Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome

Cell, Journal Year: 2023, Volume and Issue: 186(26), P. 5840 - 5858.e36

Published: Dec. 1, 2023

Short tandem repeat (STR) instability causes transcriptional silencing in several expansion disorders. In fragile X syndrome (FXS), mutation-length of a CGG STR represses FMR1 via local DNA methylation. Here, we find megabase-scale H3K9me3 domains on autosomes and encompassing the chromosome FXS patient-derived iPSCs, iPSC-derived neural progenitors, EBV-transformed lymphoblasts, brain tissue with expansion. connect inter-chromosomal interactions demarcate severe misfolding TADs loops. They harbor long synaptic genes replicating at end S phase, replication-stress-induced double-strand breaks, STRs prone to stepwise somatic instability. CRISPR engineering premutation length reverses multiple autosomes, refolds TADs, restores gene expression. can also arise normal-length iPSCs created perturbations linked genome instability, suggesting their relevance beyond FXS. Our results reveal Mb-scale heterochromatinization trans among loci susceptible

Language: Английский

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Through the lens of phase separation: intrinsically unstructured protein and chromatin looping

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

Published: Feb. 23, 2023

The establishment, maintenance and dynamic regulation of three-dimensional (3D) chromatin structures provide an important means for partitioning genome into functionally distinctive domains, which helps to define specialized gene expression programs associated with developmental stages cell types. Increasing evidence supports critical roles intrinsically disordered regions (IDRs) harbored within transcription factors (TFs) chromatin-modulatory proteins in inducing phase separation, a phenomenon forming membrane-less condensates through biomolecules. Such process is also critically involved the establishment high-order looping. IDR- separation-driven 3D (re)organization often goes wrong disease such as cancer. This review discusses about recent advances understanding how separation (IDPs) modulates looping expression.

Language: Английский

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Identifying associations between short tandem repeat sequences and gene expression in yeast reveals specific repeated motifs encoding transcriptional regulatory proteins

Computational and Structural Biotechnology Journal, Journal Year: 2025, Volume and Issue: 27, P. 705 - 716

Published: Jan. 1, 2025

Tandem repeat sequences (TRs), a class of repetitive genomic elements, are broadly distributed in both coding and non-coding regions. Investigating the relationship between function is essential for understanding genome. Saccharomyces cerevisiae serves as vital model organism widely used an engineered strain. Although transcriptional regulatory functions TRs promoters S.cerevisiae have been elucidated, our their roles within (CDS) remains limited. In this study, we integrate RNA-seq, ChIP-seq, ATAC-seq, Hi-C, Micro-C data from to analyze types distribution TRs, impact on gene expression. Our results indicate that genes containing short tandem repeats (STRs) CDS exhibit lower expression levels. Epigenetic analysis reveals these regions characterized by high levels repressive histone modifications low activating marks, with reduced chromatin accessibility fewer interactions. Furthermore, trinucleotide hexanucleotide repeated motifs STR found primarily enriched encoding proteins. This study provides new insights into characteristics STRs S.cerevisiae. The identification key offers potential targets design elements.

Language: Английский

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Interplay between CTCF-binding and CTCF-lacking regulatory elements in generating an architectural stripe at the Igh locus

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

Published: March 3, 2025

Three-dimensional genome organization orchestrates recombination and transcription of immunoglobulin heavy chain (Igh) genes. The structure wild-type (WT) alleles includes a prominent architectural stripe that extends from cluster CTCF binding elements at the 3' end locus (3'CBE), suggesting interactions this with sequences throughout 2 Mb Igh TAD. Here we elucidate interplay between regulatory located in 3'Igh domain (260 kb) impact stripe. CTCF-lacking intronic enhancer, Eµ, promotes formation tethers sub-TADs flanking CTCF-bound 3'CBE IGCR1. Substituting Eµ an EF1α promoter different orientations partially recapitulates epigenetic features WT alleles, including active histone modifications, sub-TAD 3'CBE, but does not restore VDJ recombination. Loss IGCR1 increases while inverting redirects away locus. However, inverted continue to serve as boundary against aberrant activation genes outside by Eµ. Our observations provide insights into mechanisms which modulate chromatin formation.

Language: Английский

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Identification and Characterization of LINE and SINE Retrotransposons in the African Hedgehog (Atelerix albiventris, Erinaceidae) and Their Association with 3D Genome Organization and Gene Expression

Genes, Journal Year: 2025, Volume and Issue: 16(4), P. 397 - 397

Published: March 29, 2025

Background: The African hedgehog (Atelerix albiventris) exhibits specialized skin differentiation leading to spine formation, yet its regulatory mechanisms remain unclear. Transposable elements (TEs), particularly LINEs (long interspersed nuclear elements) and SINEs (short elements), are known influence genome organization gene regulation. Objectives: Given the high proportion of in genome, this study aims characterize distribution, evolutionary dynamics, potential roles SINEs, focusing on their associations with chromatin architecture, DNA methylation, expression. Methods: We analyzed LINE SINE distribution using HiFi sequencing classified TE families through phylogenetic reconstruction. Hi-C data were used explore interactions while whole-genome 5mCpG methylation was inferred from PacBio reads muscle tissue a deep-learning-based approach. RNA-seq tissues assess expression genes linked development. Results: form distinct genomic blocks GC-rich highly methylated regions, whereas enriched AT-rich, hypomethylated regions. associated differently A/B compartments, euchromatin heterochromatin. Methylation analysis suggests that younger TEs tend have higher levels, indicates some differentially expressed may be involved epidermal skeletal Conclusions: This provides genome-wide perspective patterns, A. albiventris. While not establishing direct causal link, findings suggest development, offering basis for future functional studies.

Language: Английский

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