Chd1 protects genome integrity at promoters to sustain hypertranscription in embryonic stem cells

Bulut-Karslıoğlu, Aydan; Hu, Jin; Kim, Yun-Kyo; Cho, Brandon; Guzman-Ayala, Marcela; Williamson, Andrew J.K.; Hejna, Miroslav; Stötzel, Maximilian; Whetton, Anthony D.; Song, Jun S.; Ramalho-Santos, Miguel

doi:10.1038/s41467-021-25088-3

Cited by 10 publications

(4 citation statements)

References 44 publications

(77 reference statements)

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“…The importance of global transcriptional change in development and disease is being increasingly recognized, especially following the advent of methods that enabled their detection in primary human tumour samples and adult tissues 2 – 4 . As aforementioned, little is known about how absolute transcription levels are regulated, and most known regulators to date are those that initiate hypertranscription 7 , 9 , 47 , 48 . In this regard, our finding that TOP1 exerts a gene repressive function to counteract transcription overdrive is significant.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription

Lau,

Hu,

Zhao

et al. 2023

Nat Commun

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Regulation of global transcription output is important for normal development and disease, but little is known about the mechanisms involved. DNA topoisomerase I (TOP1) is an enzyme well-known for its role in relieving DNA supercoils for enabling transcription. Here, we report a non-enzymatic function of TOP1 that downregulates RNA synthesis. This function is dependent on specific DNA-interacting residues located on a conserved protein surface. A loss-of-function knock-in mutation on this surface, R548Q, is sufficient to cause hypertranscription and alter differentiation outcomes in mouse embryonic stem cells (mESCs). Hypertranscription in mESCs is accompanied by reduced TOP1 chromatin binding and change in genomic supercoiling. Notably, the mutation does not impact TOP1 enzymatic activity; rather, it diminishes TOP1-DNA binding and formation of compact protein-DNA structures. Thus, TOP1 exhibits opposing influences on transcription through distinct activities which are likely to be coordinated. This highlights TOP1 as a safeguard of appropriate total transcription levels in cells.

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Section: Discussionmentioning

confidence: 99%

Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription

Lau,

Hu,

Zhao

et al. 2023

Nat Commun

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“…We defined 5,810 differentially expressed mRNAs across all RNA-seq datasets and 4,406 differentially transcribed mRNAs across all TT-seq datasets (log 2 (FC) ≥0.75 & FDR≤0.05; Figure 1C-D, Figure S2C-D). RNA-seq and TT-seq datasets show similar mRNA profiles apart from five depletions, three of which have been shown to regulate mRNA processing (TTF2 51 ) or nascent transcription (CHD1, BTAF1 [52][53][54] ;…”

Section: Nucleosome Remodelers Collectively Regulate the Transcriptio...mentioning

confidence: 97%

Widespread impact of nucleosome remodelers on transcription at cis-regulatory elements

Patty,

Hainer

2024

Preprint

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Nucleosome remodeling complexes and other regulatory factors work in concert to build a chromatin environment that directs the expression of a distinct set of genes in each cell using cis-regulatory elements (CREs), such as promoters and enhancers, that drive transcription of both mRNAs and CRE-associated non-coding RNAs (ncRNAs). Two classes of CRE-associated ncRNAs include upstream antisense RNAs (uaRNAs), which are transcribed divergently from a shared mRNA promoter, and enhancer RNAs (eRNAs), which are transcribed bidirectionally from active enhancers. The complicated network of CRE regulation by nucleosome remodelers remains only partially explored, with a focus on a select, limited number of remodelers. We endeavored to elucidate a remodeler-based regulatory network governing CRE-associated transcription (mRNA, eRNA, and uaRNA) in murine embryonic stem (ES) cells to test the hypothesis that many SNF2-family nucleosome remodelers collaborate to regulate the coding and non-coding transcriptome via alteration of underlying nucleosome architecture. Using depletion followed by transient transcriptome sequencing (TT-seq), we identified thousands of misregulated mRNAs and CRE-associated ncRNAs across the remodelers examined, identifying novel contributions by understudied remodelers in the regulation of coding and non-coding transcription. Our findings suggest that mRNA and eRNA transcription are coordinately co-regulated, while mRNA and uaRNAs sharing a common promoter are independently regulated. Subsequent mechanistic studies suggest that while remodelers SRCAP and CHD8 modulate transcription through classical mechanisms such as transcription factors and histone variants, a broad set of remodelers including SMARCAL1 indirectly contribute to transcriptional regulation through maintenance of genomic stability and proper Integrator complex localization. This study systematically examines the contribution of SNF2-remodelers to the CRE-associated transcriptome, identifying at least two classes for remodeler action.

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“…For example, one such mechanism is through CHD1, a chromatin remodelling protein that is essential for transcription in mouse epiblasts [ 127 ]. CHD1 also interacts with ATM, PARP1, KAP1, and Topoisomerase 2β and remodels nucleosomes at GC-rich promoters to repair replication-induced DSBs that develop at transcription start sites [ 128 ]. By facilitating the resolution of DSBs, CHD1 can couple a global increase in transcriptional output to genome stability enabling sustained proliferation during embryogenesis.…”

Section: Dna Damage Repair In Non-transformed Stem Cellsmentioning

confidence: 99%

DNA Repair and Therapeutic Strategies in Cancer Stem Cells

Gillespie

Ward

Davies

2023

Cancers

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First-line cancer treatments successfully eradicate the differentiated tumour mass but are comparatively ineffective against cancer stem cells (CSCs), a self-renewing subpopulation thought to be responsible for tumour initiation, metastasis, heterogeneity, and recurrence. CSCs are thus presented as the principal target for elimination during cancer treatment. However, CSCs are challenging to drug target because of numerous intrinsic and extrinsic mechanisms of drug resistance. One such mechanism that remains relatively understudied is the DNA damage response (DDR). CSCs are presumed to possess properties that enable enhanced DNA repair efficiency relative to their highly proliferative bulk progeny, facilitating improved repair of double-strand breaks induced by radiotherapy and most chemotherapeutics. This can occur through multiple mechanisms, including increased expression and splicing fidelity of DNA repair genes, robust activation of cell cycle checkpoints, and elevated homologous recombination-mediated DNA repair. Herein, we summarise the current knowledge concerning improved genome integrity in non-transformed stem cells and CSCs, discuss therapeutic opportunities within the DDR for re-sensitising CSCs to genotoxic stressors, and consider the challenges posed regarding unbiased identification of novel DDR-directed strategies in CSCs. A better understanding of the DDR mediating chemo/radioresistance mechanisms in CSCs could lead to novel therapeutic approaches, thereby enhancing treatment efficacy in cancer patients.

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Chd1 protects genome integrity at promoters to sustain hypertranscription in embryonic stem cells

Cited by 10 publications

References 44 publications

Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription

Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription

Widespread impact of nucleosome remodelers on transcription at cis-regulatory elements

DNA Repair and Therapeutic Strategies in Cancer Stem Cells

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