HOTTIP-dependent R-loop formation regulates CTCF boundary activity and TAD integrity in leukemia

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

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G-quadruplexes associated with R-loops promote CTCF binding

Molecular Cell, Год журнала: 2023, Номер 83(17), С. 3064 - 3079.e5

Опубликована: Авг. 7, 2023

Язык: Английский

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DHX9 helicase promotes R-loop formation in cells with impaired RNA splicing

Nature Communications, Год журнала: 2018, Номер 9(1)

Опубликована: Окт. 15, 2018

R-loops are stable nucleic acid structures that have important physiological functions, but which also pose a significant threat to genomic stability. Increased cause replication stress and chromosome fragility been associated with diseases such as neurodegeneration cancer. Although excessive feature of cells defective in RNA processing, what causes them form is unclear. Here, we demonstrate DHX9 (RNA helicase A) promotes the formation pathological non-pathological R-loops. In absence splicing factors, correlates prolonged association Polymerase II Pol II). This leads production DNA-RNA hybrid, traps on chromatin potential block DNA replication. Our data provide molecular mechanism for relevant neurodegenerative cancers deregulated processing feature.

Язык: Английский

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R-Loops Promote Antisense Transcription across the Mammalian Genome

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

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R-loop generation during transcription: Formation, processing and cellular outcomes

DNA repair, Год журнала: 2018, Номер 71, С. 69 - 81

Опубликована: Авг. 25, 2018

Язык: Английский

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