R-Loops Promote Antisense Transcription across the Mammalian Genome DOI Creative Commons

Sue Mei Tan‐Wong,

Somdutta Dhir, Nicholas Proudfoot

и другие.

Molecular Cell, Год журнала: 2019, Номер 76(4), С. 600 - 616.e6

Опубликована: Ноя. 1, 2019

Highlights•R-loops formed within plasmids promote antisense transcription in nuclear extracts•TSS of lncRNA and eRNA are often near R-loop structures sensitive to RNase H1•Preinitiation complexes associated with synthesis dependent•Many mammalian derive from promoter activitySummaryWidespread long noncoding RNA (lncRNA) overlap many protein-coding genes mammals emanate gene promoter, enhancer, termination regions. However, their origin biological purpose remain unclear. We show that these can be generated by R-loops form when nascent transcript invades the DNA duplex behind elongating polymerase II (Pol II). Biochemically, act as intrinsic Pol promoters induce de novo synthesis. Furthermore, removal across human genome H1 overexpression causes selective reduction transcription. Consequently, we predict facilitate proximal lncRNA. Not only widely damage repair, but now they have capacity may aided evolution regulation.Graphical abstract

Язык: Английский

High-resolution, strand-specific R-loop mapping via S9.6-based DNA–RNA immunoprecipitation and high-throughput sequencing DOI
Lionel A. Sanz, Frédéric Chédin

Nature Protocols, Год журнала: 2019, Номер 14(6), С. 1734 - 1755

Опубликована: Май 3, 2019

Язык: Английский

Процитировано

217
Chromatin-associated RNAs as facilitators of functional genomic interactions DOI
Xiao Li, Xiang‐Dong Fu

Nature Reviews Genetics, Год журнала: 2019, Номер 20(9), С. 503 - 519

Опубликована: Июнь 3, 2019

Язык: Английский

Процитировано

200
G-quadruplexes are transcription factor binding hubs in human chromatin DOI Creative Commons
Jochen Spiegel, Sergio Martínez Cuesta, Santosh Adhikari

и другие.

Genome biology, Год журнала: 2021, Номер 22(1)

Опубликована: Апрель 23, 2021

Abstract Background The binding of transcription factors (TF) to genomic targets is critical in the regulation gene expression. Short, double-stranded DNA sequence motifs are routinely implicated TF recruitment, but many questions remain on how site specificity governed. Results Herein, we reveal a previously unappreciated role for secondary structures as key features recruitment. In systematic, genome-wide study, discover that endogenous G-quadruplex (G4s) prevalent sites human chromatin. Certain TFs bind G4s with affinities comparable targets. We demonstrate that, chromatin context, this interaction competed out small molecule. Notably, prominent large number TFs, particularly at promoters highly expressed genes. Conclusions Our results novel non-canonical mechanism whereby operate common hubs different promote increased transcription.

Язык: Английский

Процитировано

198
Senataxin Mutation Reveals How R-Loops Promote Transcription by Blocking DNA Methylation at Gene Promoters DOI Creative Commons
Christopher Grunseich, Isabel X. Wang, Jason A. Watts

и другие.

Molecular Cell, Год журнала: 2018, Номер 69(3), С. 426 - 437.e7

Опубликована: Янв. 27, 2018

Язык: Английский

Процитировано

188
Regulation of long non-coding RNAs and genome dynamics by the RNA surveillance machinery DOI

Lekha Nair,

Hachung Chung, Uttiya Basu

и другие.

Nature Reviews Molecular Cell Biology, Год журнала: 2020, Номер 21(3), С. 123 - 136

Опубликована: Фев. 4, 2020

Язык: Английский

Процитировано

177
Human proteins that interact with RNA/DNA hybrids DOI Creative Commons
Isabel X. Wang, Christopher Grunseich,

Jennifer E. Fox

и другие.

Genome Research, Год журнала: 2018, Номер 28(9), С. 1405 - 1414

Опубликована: Авг. 14, 2018

RNA/DNA hybrids form when RNA hybridizes with its template DNA generating a three-stranded structure known as the R-loop. Knowledge of how they and resolve, well their functional roles, is limited. Here, by pull-down assays followed mass spectrometry, we identified 803 proteins that bind to hybrids. Because these were using in vitro assays, confirmed R-loops vivo. They include are involved variety functions, including most steps processing. The enriched for K homology (KH) helicase domains. Among them, more than 300 preferred binding double-stranded DNA. These serve starting points mechanistic studies elucidate what regulate regulated.

Язык: Английский

Процитировано

164
Genome-wide mapping of G-quadruplex structures with CUT&Tag DOI Creative Commons
Jing Lyu, Rui Shao, Philip Yuk Kwong Yung

и другие.

Nucleic Acids Research, Год журнала: 2021, Номер 50(3), С. e13 - e13

Опубликована: Окт. 21, 2021

Abstract Single-stranded genomic DNA can fold into G-quadruplex (G4) structures or form DNA:RNA hybrids (R loops). Recent evidence suggests that such non-canonical affect gene expression, methylation, replication fork progression and genome stability. When how G4 are resolved remains unclear. Here we report the use of Cleavage Under Targets Tagmentation (CUT&Tag) for mapping native in mammalian cell lines at high resolution low background. Mild conditions used procedure retain more provide a higher signal-to-noise ratio than ChIP-based methods. We determine landscape mouse embryonic stem cells (ESC), observing widespread formation active promoters, poised enhancers. discover presence motifs distinguishes primed enhancers ESCs. Upon differentiation to neural progenitor (NPC), enhancer G4s lost. Further, performing R-loop CUT&Tag, demonstrate genome-wide co-occurrence single-stranded DNA, R loops promoters confirm exist independent ongoing transcription, suggesting an intricate relationship between transcription structures.

Язык: Английский

Процитировано

139
R-loops as Janus-faced modulators of DNA repair DOI
Aline Marnef, Gaëlle Legube

Nature Cell Biology, Год журнала: 2021, Номер 23(4), С. 305 - 313

Опубликована: Апрель 1, 2021

Язык: Английский

Процитировано

135
R-loop proximity proteomics identifies a role of DDX41 in transcription-associated genomic instability DOI Creative Commons
Thorsten Mosler, Francesca Conte, Gabriel M. C. Longo

и другие.

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Дек. 16, 2021

Transcription poses a threat to genomic stability through the formation of R-loops that can obstruct progression replication forks. are three-stranded nucleic acid structures formed by an RNA-DNA hybrid with displaced non-template DNA strand. We developed Proximity Proteomics map R-loop proximal proteome human cells using quantitative mass spectrometry. implicate different cellular proteins in regulation and identify role tumor suppressor DDX41 opposing double strand break accumulation promoters. is enriched promoter regions vivo, unwind hybrids vitro. upon loss accompanied stress, increase breaks transcriptome changes associated inflammatory response. Germline loss-of-function mutations lead predisposition acute myeloid leukemia adulthood. propose instability-associated response may contribute development familial AML mutated DDX41.

Язык: Английский

Процитировано

117
HOTTIP-dependent R-loop formation regulates CTCF boundary activity and TAD integrity in leukemia DOI Creative Commons
Huacheng Luo, Ganqian Zhu, Melanie A. Eshelman

и другие.

Molecular Cell, Год журнала: 2022, Номер 82(4), С. 833 - 851.e11

Опубликована: Фев. 1, 2022

HOTTIP lncRNA is highly expressed in acute myeloid leukemia (AML) driven by MLL rearrangements or NPM1 mutations to mediate HOXA topologically associated domain (TAD) formation and drive aberrant transcription. However, the mechanism through which accesses CCCTC-binding factor (CTCF) chromatin boundaries regulates CTCF-mediated genome topology remains unknown. Here, we show that directly interacts with a fraction of CTCF-binding sites (CBSs) AML recruiting CTCF/cohesin complex R-loop-associated regulators form R-loops. HOTTIP-mediated R-loops reinforce CTCF boundary facilitate TADs gene Either deleting CBS targeting RNase H eliminate β-catenin TAD impaired activity, inhibited promoter/enhancer interactions, reduced target expression, mitigated leukemogenesis xenograft mouse models expression. Thus, R-loop reinforces activity integrity oncogene transcription development.

Язык: Английский

Процитировано

78