The Role of Nucleosomes in Epigenetic Gene Regulation

Giles, Katherine A.; Taberlay, Phillippa C.

doi:10.1007/978-981-13-8958-0_4

Cited by 7 publications

(10 citation statements)

References 226 publications

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“…Nucleosomes serve as a physical backbone for chromatin organisation on a global scale and at local gene regulatory elements. Nucleosomes therefore govern both genome-wide stability and local DNA accessibility [ 1 ]. Nucleosome positioning by ATP-dependent chromatin remodellers plays a critical role in regulating DNA accessibility and allows genes to be expressed at the appropriate place and time [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

“…Nucleosomes therefore govern both genome-wide stability and local DNA accessibility [ 1 ]. Nucleosome positioning by ATP-dependent chromatin remodellers plays a critical role in regulating DNA accessibility and allows genes to be expressed at the appropriate place and time [ 1 ]. Genomic profiling has demonstrated that dynamic regulation of DNA accessibility occurs primarily at DNA regulatory elements, which are cell type specific, and that DNA accessibility changes reflect concomitant transcriptional patterns [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

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BRG1 knockdown inhibits proliferation through multiple cellular pathways in prostate cancer

et al. 2021

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Background BRG1 (encoded by SMARCA4) is a catalytic component of the SWI/SNF chromatin remodelling complex, with key roles in modulating DNA accessibility. Dysregulation of BRG1 is observed, but functionally uncharacterised, in a wide range of malignancies. We have probed the functions of BRG1 on a background of prostate cancer to investigate how BRG1 controls gene expression programmes and cancer cell behaviour. Results Our investigation of SMARCA4 revealed that BRG1 is over-expressed in the majority of the 486 tumours from The Cancer Genome Atlas prostate cohort, as well as in a complementary panel of 21 prostate cell lines. Next, we utilised a temporal model of BRG1 depletion to investigate the molecular effects on global transcription programmes. Depleting BRG1 had no impact on alternative splicing and conferred only modest effect on global expression. However, of the transcriptional changes that occurred, most manifested as down-regulated expression. Deeper examination found the common thread linking down-regulated genes was involvement in proliferation, including several known to increase prostate cancer proliferation (KLK2, PCAT1 and VAV3). Interestingly, the promoters of genes driving proliferation were bound by BRG1 as well as the transcription factors, AR and FOXA1. We also noted that BRG1 depletion repressed genes involved in cell cycle progression and DNA replication, but intriguingly, these pathways operated independently of AR and FOXA1. In agreement with transcriptional changes, depleting BRG1 conferred G1 arrest. Conclusions Our data have revealed that BRG1 promotes cell cycle progression and DNA replication, consistent with the increased cell proliferation associated with oncogenesis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BRG1 knockdown inhibits proliferation through multiple cellular pathways in prostate cancer

et al. 2021

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“…The epigenome is at the interface of genes and the environment, enabling dynamic regulation of gene expression in each cell. The 'epigenome' includes DNA methylation and histone modifications, as well as the physical organisation of DNA inside the nucleus, which dynamically regulates gene expression 6 . The combination of epigenetic elements determines whether a genomic region is active, repressed or silenced.…”

Section: Introductionmentioning

confidence: 99%

H3K4me3 enrichment defines neuronal age, while a youthful H3K27ac signature is recapitulated in aged neurons

Giles

Phipps

Cashion

et al. 2021

Preprint

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Neurons live for the lifespan of the individual and underlie our ability for lifelong learning and memory. However, aging alters neuron morphology and function resulting in age-related cognitive decline. It is well established that epigenetic alterations are essential for learning and memory, yet few neuron-specific genome-wide epigenetic maps exist into old age. Comprehensive mapping of H3K4me3 and H3K27ac in mouse neurons across lifespan revealed plastic H3K4me3 marking that differentiates neuronal age linked to known characteristics of cellular and neuronal aging. We determined that neurons in old age recapitulate the H3K27ac enrichment at promoters, enhancers and super enhancers from young adult neurons, likely representing a re-activation of pathways to maintain neuronal output. Finally, this study identified new characteristics of neuronal aging, including altered rDNA regulation and epigenetic regulatory mechanisms. Collectively, these findings indicate a key role for epigenetic regulation in neurons, that is inextricably linked with aging.

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“…Nucleosomes serve as a physical backbone for chromatin organization on a global scale and at local gene regulatory elements. Nucleosomes therefore govern both genome-wide stability and local DNA accessibility (1). Nucleosome positioning by ATP-dependent chromatin remodellers plays a critical role in regulating DNA accessibility and allows genes to be expressed at the appropriate place and time (1).…”

Section: Introductionmentioning

confidence: 99%

“…Nucleosomes therefore govern both genome-wide stability and local DNA accessibility (1). Nucleosome positioning by ATP-dependent chromatin remodellers plays a critical role in regulating DNA accessibility and allows genes to be expressed at the appropriate place and time (1). Genomic profiling has demonstrated that dynamic regulation of DNA accessibility occurs primarily at DNA regulatory elements, which are cell type specific, and that DNA accessibility changes reflect concomitant transcriptional patterns.…”

Section: Introductionmentioning

confidence: 99%

BRG1 promotes transcriptional patterns that are permissive to proliferation in cancer cells

Giles

Gould

Achinger-Kawecka

et al. 2020

Preprint

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ABSTRACTDeregulated expression of the chromatin remodeller, BRG1 (Brahma related gene 1; encoded by SMARCA4), is observed in a wide range of malignancies. Yet, the underlying function and cellular consequences of altered BRG1 expression during oncogenesis are still being uncovered. Here, we have investigated a role for BRG1 in directing genome-wide transcription programs in the context of prostate cancer. We examined The Cancer Genome Atlas (TCGA) prostate cancer cohort and a panel of prostate cell lines and found SMARCA4 was consistently overexpressed irrespective of Gleason grade or molecular subtype. We then tested the effect of BRG1 depletion on transcriptional patterns in LNCaP prostate cancer cells. This revealed BRG1 depletion does not impact alternative splicing and surprisingly, confers only a modest effect on global gene expression. Of the transcriptional changes that did occur, most manifested as down-regulated gene expression with striking enrichment of multiple genes involved in cell cycle progression, and those that have previously been associated with prostate cancer proliferation. We found BRG1 regulated genes could be defined by the presence or absence of AR and FOXA1 occupancy at their cognate gene promoters. Genes co-regulated by BRG1, AR and FOXA1 include known prostate cancer genes KLK2, PCAT1 and VAV3. Genes regulated by BRG1 independently of AR and FOXA1 include several proliferation and DNA replication factors. In agreement with the transcriptional changes, depleting BRG1 conferred G1 arrest. Together, these data show that BRG1 regulates transcription of proliferative and oncogenic factors, providing mechanistic insight into the function of BRG1 in prostate cancer cells.

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The Role of Nucleosomes in Epigenetic Gene Regulation

Cited by 7 publications

References 226 publications

BRG1 knockdown inhibits proliferation through multiple cellular pathways in prostate cancer

BRG1 knockdown inhibits proliferation through multiple cellular pathways in prostate cancer

H3K4me3 enrichment defines neuronal age, while a youthful H3K27ac signature is recapitulated in aged neurons

BRG1 promotes transcriptional patterns that are permissive to proliferation in cancer cells

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