The 3D chromatin landscape of rhabdomyosarcoma

Wang, Meng; Sreenivas, Prethish; Sunkel, Benjamin D.; Wang, Long; Ignatius, Myron S.

doi:10.1093/narcan/zcad028

Cited by 7 publications

(5 citation statements)

References 82 publications

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“…2A right and 3 A). 21 The analysis of this site across published chromatin data sets from ENCODE indicated that this is a well-conserved element in all cell types assessed and harbors a potential chromatin subdomain containing the NOTCH1 gene.…”

Section: Resultsmentioning

confidence: 95%

A SNAI2/CTCF Interaction is Required for NOTCH1 Expression in Rhabdomyosarcoma

Sreenivas,

Wang,

Wang

et al. 2023

Molecular and Cellular Biology

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Rhabdomyosarcoma (RMS) is a pediatric malignancy of the muscle with characteristics of cells blocked in differentiation. NOTCH1 is an oncogene that promotes self-renewal and blocks differentiation in the fusion negative-RMS sub-type. However, how NOTCH1 expression is transcriptionally maintained in tumors is unknown. Analyses of SNAI2 and CTCF chromatin binding and HiC analyses revealed a conserved SNAI2/CTCF overlapping peak downstream of the NOTCH1 locus marking a sub-topologically associating domain (TAD) boundary. Deletion of the SNAI2-CTCF peak showed that it is essential for NOTCH1 expression and viability of FN-RMS cells. Reintroducing constitutively activated NOTCH1 -ΔE in cells with the SNAI2-CTCF peak deleted restored cell-viability. Ablation of SNAI2 using CRISPR/Cas9 reagents resulted in the loss of majority of RD and SMS-CTR FN-RMS cells. However, the few surviving clones that repopulate cultures have recovered NOTCH1 . Cells that re-establish NOTCH1 expression after SNAI2 ablation are unable to differentiate robustly as SNAI2 shRNA knockdown cells; yet, SNAI2 -ablated cells continued to be exquisitely sensitive to ionizing radiation. Thus, we have uncovered a novel mechanism by which SNAI2 and CTCF maintenance of a sub-TAD boundary promotes rather than represses NOTCH1 expression. Further, we demonstrate that SNAI2 suppression of apoptosis post-radiation is independent of SNAI2 / NOTCH1 effects on self-renewal and differentiation.

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Section: Resultsmentioning

confidence: 95%

A SNAI2/CTCF Interaction is Required for NOTCH1 Expression in Rhabdomyosarcoma

Sreenivas,

Wang,

Wang

et al. 2023

Molecular and Cellular Biology

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“…It also suggests that analysis of gene regulation and expression in RMS cells considered on the basis of the spatial positioning of the chromosomes they reside on, rather than by clustering genes on the basis of similar function or biological processes, would demonstrate chromosome-specific differences. Others have elucidated characteristics of the organization of the genome in rhabdomyosarcoma cells using techniques including Hi-C, ChiP-Seq, and AQuA-HiChIP (Vicente-Garcia et al, 2017;Gryder et al, 2019;Wang et al, 2023). While these sequencingbased techniques have characterized aspects such as transcription factor binding, interacting genomic regions, histone marks, and regulatory elements such as enhancers, they do not directly assess chromosomal positioning or changes in such positioning, highlighting the need for dedicated analyses of spatial nuclear organization in the cells.…”

Section: Discussionmentioning

confidence: 99%

Differentiation-dependent chromosomal organization changes in normal myogenic cells are absent in rhabdomyosarcoma cells

Ibarra,

Hershenhouse,

Almassalha

et al. 2023

Front. Cell Dev. Biol.

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Myogenesis, the progression of proliferating skeletal myoblasts to terminally differentiated myotubes, regulates thousands of target genes. Uninterrupted linear arrays of such genes are differentially associated with specific chromosomes, suggesting chromosome specific regulatory roles in myogenesis. Rhabdomyosarcoma (RMS), a tumor of skeletal muscle, shares common features with normal muscle cells. We hypothesized that RMS and myogenic cells possess differences in chromosomal organization related to myogenic gene arrangement. We compared the organizational characteristics of chromosomes 2 and 18, chosen for their difference in myogenic gene arrangement, in cultured RMS cell lines and normal myoblasts and myotubes. We found chromosome-specific differences in organization during normal myogenesis, with increased area occupied and a shift in peripheral localization specifically for chromosome 2. Most strikingly, we found a differentiation-dependent difference in positioning of chromosome 2 relative to the nuclear axis, with preferential positioning along the major nuclear axis present only in myotubes. RMS cells demonstrated no preference for such axial positioning, but induced differentiation through transfection of the pro-myogenic miRNA miR-206 resulted in an increase of major axial positioning of chromosome 2. Our findings identify both a differentiation-dependent, chromosome-specific change in organization in normal myogenesis, and highlight the role of chromosomal spatial organization in myogenic differentiation.

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“…We highlight several of these insights here. Despite “quieter” genomes in sarcoma (lacking high mutation rates), there has been recent compelling evidence that structural variation (SV) is much more common in sarcoma than previously thought, including but not limited to the definitional translocation events ( Chen et al, 2015 ; Gryder et al, 2020a ; Nacev et al, 2022 ; Shukla et al, 2022 ; Xu et al, 2022 ; Choo et al, 2023 ; Wang et al, 2023 ). We anticipate exciting advances in the coming years of deeper characterization of SV in diverse sarcomas, enabled in part by emerging innovative sequencing technologies and platforms.…”

Section: Introductionmentioning

confidence: 99%

“…The depth and power of these clinical genomics studies will enable researchers to uncover key mechanisms of sarcomagenesis in the coming years. Moreover, as we transition from examining linear genomic landscapes into the examination of 3-dimensional (3D) epigenomic landscapes ( Gryder et al, 2020a ; Wang et al, 2023 ; Kim et al, 2024 ), we will begin to integrate genetic and epigenetic mechanisms driving diverse sarcomas.…”

Section: Introductionmentioning

confidence: 99%

“…The spreading of histone acetylation, upon HDAC inhibition, leads to the disruption of 3D chromatin architecture, which can be precisely quantified by AQuA-HiChIP ( Gryder et al, 2020a ). To provide a chromatin domain context for the local functions of tumor-essential TFs in RMS, a newly reported comprehensive 3D chromatin analysis has uncovered the large chromatin compartments and domains in which these regulatory functions are executed ( Wang et al, 2023 ). Therapeutic targeting of Ras pathway activity ( Yohe et al, 2018 ), histone acetylation ( Gryder et al, 2019a ; Gryder et al, 2019b ; Gryder et al, 2020a ; Gryder et al, 2020b ) and lysine demethylase inhibition ( Kim et al, 2024 ) halt RMS transcriptional activity thus impairing RMS growth.…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic determinants of fusion-driven sarcomas: paradigms and challenges

Stanton,

Pomella

2024

Front. Cell Dev. Biol.

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We describe exciting recent advances in fusion-driven sarcoma etiology, from an epigenetics perspective. By exploring the current state of the field, we identify and describe the central mechanisms that determine sarcomagenesis. Further, we discuss seminal studies in translational genomics, which enabled epigenetic characterization of fusion-driven sarcomas. Important context for epigenetic mechanisms include, but are not limited to, cell cycle and metabolism, core regulatory circuitry, 3-dimensional chromatin architectural dysregulation, integration with ATP-dependent chromatin remodeling, and translational animal modeling. Paradoxically, while the genetic requirements for oncogenic transformation are highly specific for the fusion partners, the epigenetic mechanisms we as a community have uncovered are categorically very broad. This dichotomy prompts the question of whether the investigation of rare disease epigenomics should prioritize studying individual cell populations, thereby examining whether the mechanisms of chromatin dysregulation are specific to a particular tumor. We review recent advances focusing on rhabdomyosarcoma, synovial sarcoma, alveolar soft part sarcoma, clear cell sarcoma, undifferentiated round cell sarcoma, Ewing sarcoma, myxoid/round liposarcoma, epithelioid hemangioendothelioma and desmoplastic round cell tumor. The growing number of groundbreaking discoveries in the field, motivated us to anticipate further exciting advances in the area of mechanistic epigenomics and direct targeting of fusion transcription factors in the years ahead.

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The 3D chromatin landscape of rhabdomyosarcoma

Cited by 7 publications

References 82 publications

A SNAI2/CTCF Interaction is Required for NOTCH1 Expression in Rhabdomyosarcoma

A SNAI2/CTCF Interaction is Required for NOTCH1 Expression in Rhabdomyosarcoma

Differentiation-dependent chromosomal organization changes in normal myogenic cells are absent in rhabdomyosarcoma cells

Epigenetic determinants of fusion-driven sarcomas: paradigms and challenges

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