TASOR expression in naive embryonic stem cells safeguards their developmental potential DOI Creative Commons
Carlos A. Pinzón-Arteaga, Ryan O’Hara, Alice Mazzagatti

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(11), P. 114887 - 114887

Published: Oct. 24, 2024

Language: Английский

Asymmetric distribution of parental H3K9me3 in S phase silences L1 elements DOI
Zhiming Li, Shoufu Duan, Xu Hua

et al.

Nature, Journal Year: 2023, Volume and Issue: 623(7987), P. 643 - 651

Published: Nov. 8, 2023

Language: Английский

Citations

26
Enhancer cooperativity can compensate for loss of activity over large genomic distances DOI Creative Commons
Henry Thomas, Songjie Feng,

Felix Haslhofer

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 1, 2024

Enhancers are short DNA sequences that activate their target promoter from a distance; however, increasing the genomic distance between enhancer and decreases expression levels. Many genes controlled by combinations of multiple enhancers, yet interaction cooperation individual elements not well understood. Here, we developed synthetic platform in mouse embryonic stem cells allows building complex regulatory landscapes bottom up. We tested system integrating enhancers at different distances confirmed strength an contributes to how strongly it is affected increased distance. Furthermore, synergy two depends on which integrated: introducing weak strong increases reporter gene expression, allowing distances.

Language: Английский

Citations

8
PP1 PNUTS binds the restrictor and dephosphorylates RNA pol II CTD Ser5 to stimulate transcription termination DOI
Benjamin Erickson, Roman O. Fedoryshchak,

Nova Fong

et al.

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

Published: July 13, 2024

Abstract The restrictor, ZC3H4/WDR82, is the major termination factor for antisense transcription from bidirectional promoters, but its mechanism poorly understood. We report that ZC3H4/WDR82 co-purifies with PP1 phosphatase and nuclear targeting subunit, PNUTS, which binds directly to WDR82 subunit of restrictor. AlphaFold predicts a quaternary complex, PPWZ, in P P1-associated NUTS Z C3H4 both contact W DR82. To investigate role protein dephosphorylation PPWZ activity, we expressed substrate trap comprising inactive H66K linked PNUTS C-terminus. -PNUTS pol II large exosome components. -PNUTS, not WT functions as dominant-negative inhibitor CTD Ser5 dephosphorylation. Both these activities require binding domain interacts show hyperphosphorylation associated higher processivity reduced pausing would counteract termination, propose by coupled termination. In summary, identify activity complex essential terminator function this heterotetramer physiologically relevant form

Language: Английский

Citations

6
DNA methylation governs the sensitivity of repeats to restriction by the HUSH-MORC2 corepressor DOI Creative Commons
Ninoslav Pandiloski, Vivien Horváth, Ofelia Karlsson

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 30, 2024

The human silencing hub (HUSH) complex binds to transcripts of LINE-1 retrotransposons (L1s) and other genomic repeats, recruiting MORC2 effectors remodel chromatin. How HUSH operate alongside DNA methylation, a central epigenetic regulator repeat transcription, remains largely unknown. Here we interrogate this relationship in neural progenitor cells (hNPCs), somatic model brain development that tolerates removal methyltransferase DNMT1. Upon loss or subunit TASOR hNPCs, L1s remain silenced by robust promoter methylation. However, genome demethylation activation evolutionarily-young attracts binding, simultaneous depletion DNMT1 causes massive accumulation L1 transcripts. We identify the same mechanistic hierarchy at pericentromeric α-satellites clustered protocadherin genes, repetitive elements important for chromosome structure neurodevelopment respectively. Our data delineate control repeats cells, with implications understanding vital functions HUSH-MORC2 hypomethylated contexts throughout development.

Language: Английский

Citations

5
Long-range regulation of transcription scales with genomic distance in a gene-specific manner DOI Creative Commons
Christina L Jensen, Liangfu Chen, Tomek Swigut

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 1, 2024

Although critical for tuning the timing and level of transcription, enhancer communication with distal promoters is not well understood. Here, we bypass need sequence-specific transcription factors (TFs) recruit activators directly using a chimeric array gRNA oligos to target dCas9 fused activator VP64-p65-Rta (CARGO-VPR). We show that this approach achieves effective recruitment arbitrary genomic sites, even those inaccessible when targeted single guide. utilize CARGO-VPR across Prdm8-Fgf5 locus in mouse embryonic stem cells (mESCs), where neither gene expressed. any tested region results transcriptional induction at least one gene, expression strongly depends on distance between promoter site. However, expression-distance relationship each scales distinctly manner attributable differences 3D contact frequency, DNA sequence, or presence repressive chromatin marks locus.

Language: Английский

Citations

5
mRNA nuclear export: how mRNA identity features distinguish functional RNAs from junk transcripts DOI Creative Commons
Alexander F. Palazzo, Yi Qiu,

Yoon Mo Kang

et al.

RNA Biology, Journal Year: 2023, Volume and Issue: 21(1), P. 1 - 12

Published: Dec. 13, 2023

The division of the cellular space into nucleoplasm and cytoplasm promotes quality control mechanisms that prevent misprocessed mRNAs junk RNAs from gaining access to translational machinery. Here, we explore how properly processed are distinguished both by presence or absence various 'identity features'.

Language: Английский

Citations

12
PP1/PNUTS Phosphatase Binds the Restrictor Complex and Stimulates RNA pol II Transcription Termination DOI
Benjamin Erickson, Roman O. Fedoryshchak,

Nova Fong

et al.

Published: Jan. 1, 2025

The restrictor, ZC3H4/WDR82, terminates antisense transcription from bidirectional promoters, but its mechanism is poorly understood. We report that ZC3H4/WDR82 immunoprecipitate with PP1 phosphatase and nuclear targeting subunit, PNUTS, which binds to WDR82. AlphaFold predicts a complex of PP1/PNUTS restrictor where both PNUTS ZC3H4 contact A substrate trap, PP1H66K-PNUTS, comprising inactive fused the C-terminus antagonizes mediated termination whereas PP1WT-PNUTS has less effect suggesting activity required for termination. One implicated in by pol II CTD Ser5-P. PP1H66K-PNUTS induces Ser5-P hyperphosphorylation at 5' ends presumably inhibiting dephosphorylation. NET-seq analysis suggests Ser5 dephosphorylation would promote increasing pausing. Both inhibition require WDR82 binding domain mediates binding. In summary, associated via promotes efficient

Language: Английский

Citations

0
PP1/PNUTS phosphatase binds the restrictor complex and stimulates RNA Pol II transcription termination DOI
Benjamin Erickson, Roman O. Fedoryshchak,

Nova Fong

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(5), P. 115564 - 115564

Published: April 16, 2025

Language: Английский

Citations

0
Multiple Forms and Functions of Premature Termination by RNA Polymerase II DOI
David L. Bentley

Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: unknown, P. 168743 - 168743

Published: Aug. 1, 2024

Language: Английский

Citations

3
HLTF resolves G4s and promotes G4-induced replication fork slowing to maintain genome stability DOI
Gongshi Bai, Theresa Endres, Ulrike Kühbacher

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(16), P. 3044 - 3060.e11

Published: Aug. 1, 2024

Language: Английский

Citations

3