ORCID Profile
0000-0001-5909-5452
Current Organisation
Children's Medical Research Institute
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Publisher: Cold Spring Harbor Laboratory
Date: 04-07-2020
DOI: 10.1101/2020.07.03.187385
Abstract: 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 programs and cancer cell behaviour. Our investigation of SMARCA4 revealed that BRG1 is universally overexpressed in 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 programs. Unexpectedly, 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 oncogenic 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. Our data have revealed that BRG1 has capacity to drive oncogenesis by coordinating oncogenic pathways dependent on BRG1 for proliferation, cell cycle progression and DNA replication.
Publisher: Cold Spring Harbor Laboratory
Date: 06-04-2016
Abstract: A three-dimensional chromatin state underpins the structural and functional basis of the genome by bringing regulatory elements and genes into close spatial proximity to ensure proper, cell-type–specific gene expression profiles. Here, we performed Hi-C chromosome conformation capture sequencing to investigate how three-dimensional chromatin organization is disrupted in the context of copy-number variation, long-range epigenetic remodeling, and atypical gene expression programs in prostate cancer. We find that cancer cells retain the ability to segment their genomes into megabase-sized topologically associated domains (TADs) however, these domains are generally smaller due to establishment of additional domain boundaries. Interestingly, a large proportion of the new cancer-specific domain boundaries occur at regions that display copy-number variation. Notably, a common deletion on 17p13.1 in prostate cancer spanning the TP53 tumor suppressor locus results in bifurcation of a single TAD into two distinct smaller TADs. Change in domain structure is also accompanied by novel cancer-specific chromatin interactions within the TADs that are enriched at regulatory elements such as enhancers, promoters, and insulators, and associated with alterations in gene expression. We also show that differential chromatin interactions across regulatory regions occur within long-range epigenetically activated or silenced regions of concordant gene activation or repression in prostate cancer. Finally, we present a novel visualization tool that enables integrated exploration of Hi-C interaction data, the transcriptome, and epigenome. This study provides new insights into the relationship between long-range epigenetic and genomic dysregulation and changes in higher-order chromatin interactions in cancer.
Publisher: Cold Spring Harbor Laboratory
Date: 24-06-2022
DOI: 10.1101/2022.06.24.497492
Abstract: Faithful DNA replication requires the orderly firing of replication origins across the genome. At present, we lack details around how origins are selected for activation and the subsequent impact of this on replication dynamics. Here, we have investigated how chromatin organisation contributes to replication initiation and dynamics by intersecting ChIP-seq, Hi-C, Repli-seq, and OK-seq data from primary and tumour cells lines. We found replication initiation is significantly enriched at TAD boundaries, co-localizing with CTCF and cohesin in early and mid S-phase. Strong replication fork directionality (RFD) from initiation zones in TAD boundaries could occur in a bi- or uni-directional manner, which highly correlated with replication timing. While TAD boundaries were largely invariant, a minority of initiation zones were shared across cell lines, indicative of cell type specific regulation. These data are consistent with chromatin structure organizing replication initiation and dynamics, ensuring orderly completion of replication from TAD boundaries into TAD internal regions.
Publisher: Springer Science and Business Media LLC
Date: 17-02-2021
DOI: 10.1186/S13148-021-01023-7
Abstract: 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. 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. Our data have revealed that BRG1 promotes cell cycle progression and DNA replication, consistent with the increased cell proliferation associated with oncogenesis.
Publisher: Future Medicine Ltd
Date: 08-2014
DOI: 10.2217/EPI.14.37
Abstract: Chromatin remodeler complexes exhibit the ability to alter nucleosome composition and positions, with seemingly ergent roles in the regulation of chromatin architecture and gene expression. The outcome is directed by subunit variation and interactions with accessory factors. Recent studies have revealed that subunits of chromatin remodelers display an unexpectedly high mutation rate and/or are inactivated in a number of cancers. Consequently, a repertoire of epigenetic processes are likely to be affected, including interactions with histone modifying factors, as well as the ability to precisely modulate nucleosome positions, DNA methylation patterns and potentially, higher-order genome structure. However, the true significance of chromatin remodeler genetic aberrations in promoting a cascade of epigenetic changes, particularly during initiation and progression of cancer, remains largely unknown.
Publisher: Elsevier
Date: 2018
Publisher: Oxford University Press (OUP)
Date: 08-2019
DOI: 10.1093/BIOINFORMATICS/BTY675
Abstract: A synoptic view of the human genome benefits chiefly from the application of nucleic acid sequencing and microarray technologies. These platforms allow interrogation of patterns such as gene expression and DNA methylation at the vast majority of canonical loci, allowing granular insights and opportunities for validation of original findings. However, problems arise when validating against a “gold standard” measurement, since this immediately biases all subsequent measurements towards that particular technology or protocol. Since all genomic measurements are estimates, in the absence of a ”gold standard” we instead empirically assess the measurement precision and sensitivity of a large suite of genomic technologies via a consensus modelling method called the row-linear model. This method is an application of the American Society for Testing and Materials Standard E691 for assessing interlaboratory precision and sources of variability across multiple testing sites. Both cross-platform and cross-locus comparisons can be made across all common loci, allowing identification of technology- and locus-specific tendencies. We assess technologies including the Infinium MethylationEPIC BeadChip, whole genome bisulfite sequencing (WGBS), two different RNA-Seq protocols (PolyA+ and Ribo-Zero) and five different gene expression array platforms. Each technology thus is characterised herein, relative to the consensus. We showcase a number of applications of the row-linear model, including correlation with known interfering traits. We demonstrate a clear effect of cross-hybridisation on the sensitivity of Infinium methylation arrays. Additionally, we perform a true interlaboratory test on a set of s les interrogated on the same platform across twenty-one separate testing laboratories. A full implementation of the row-linear model, plus extra functions for visualisation, are found in the R package consensus at impeters82/consensus. Supplementary data are available at Bioinformatics online.
Publisher: Springer Singapore
Date: 2019
Publisher: Springer Science and Business Media LLC
Date: 11-07-2023
DOI: 10.1038/S41388-023-02773-9
Abstract: The chromatin remodeler SMARCA4 /BRG1 is a key epigenetic regulator with erse roles in coordinating the molecular programs that underlie brain tumour development. BRG1 function in brain cancer is largely specific to the tumour type and varies further between tumour subtypes, highlighting its complexity. Altered SMARCA4 expression has been linked to medulloblastoma, low-grade gliomas such as oligodendroglioma, high-grade gliomas such as glioblastoma and atypical/teratoid rhabdoid tumours. SMARCA4 mutations in brain cancer predominantly occur in the crucial catalytic ATPase domain, which is associated with tumour suppressor activity. However, SMARCA4 is opposingly seen to promote tumourigenesis in the absence of mutation and through overexpression in other brain tumours. This review explores the multifaceted interaction between SMARCA4 and various brain cancer types, highlighting its roles in tumour pathogenesis, the pathways it regulates, and the advances that have been made in understanding the functional relevance of mutations. We discuss developments made in targeting SMARCA4 and the potential to translate these to adjuvant therapies able to enhance current methods of brain cancer treatment.
Publisher: Oxford University Press (OUP)
Date: 11-2015
DOI: 10.1095/BIOLREPROD.115.132241
Abstract: While estrogen action is the major driver of uterine development, androgens acting via the androgen receptor (AR) may also promote uterine growth as suggested by uterine phenotypes in global AR knockout (ARKO) female mice. Because AR is expressed in uterine endometrial glands, we generated (Cre/loxP) uterine gland epithelium-specific ARKO (ugeARKO) to determine the role of endometrial gland-specific androgen actions. However, AR in uterine gland epithelium may not be required for normal uterine development and function because ugeARKO females had normal uterine development and fertility. To determine if exogenous androgens acting via AR can fully support uterine growth in the absence of estrogens, the ARKO and ugeARKO females were ovariectomized and treated with supraphysiological doses of testosterone or dihydrotestosterone (nonaromatizable androgen). Both dihydrotestosterone and testosterone supported full uterine regrowth in wild-type females while ARKO females had no regrowth (comparable to ovariectomized only). These findings suggest that androgens acting via AR can promote full uterine regrowth in the absence of estrogens. The ugeARKO had 50% regrowth when compared to intact uterine glands, and histomorphologically, both the endometrial and myometrial areas were significantly (P < 0.05) reduced, suggesting glandular epithelial AR located in the endometrium may indirectly modify myometrial development. Additionally, to confirm Cre function in endometrial glands, we generated uge-specific PTEN knockout mouse model. The ugePTEN knockout females developed severe endometrial hyperplasia and therefore present a novel model for future research.
Publisher: Springer Science and Business Media LLC
Date: 12-02-2019
Publisher: Springer Science and Business Media LLC
Date: 16-01-2020
DOI: 10.1038/S41467-019-14098-X
Abstract: Endocrine therapy resistance frequently develops in estrogen receptor positive (ER+) breast cancer, but the underlying molecular mechanisms are largely unknown. Here, we show that 3-dimensional (3D) chromatin interactions both within and between topologically associating domains (TADs) frequently change in ER+ endocrine-resistant breast cancer cells and that the differential interactions are enriched for resistance-associated genetic variants at CTCF-bound anchors. Ectopic chromatin interactions are preferentially enriched at active enhancers and promoters and ER binding sites, and are associated with altered expression of ER-regulated genes, consistent with dynamic remodelling of ER pathways accompanying the development of endocrine resistance. We observe that loss of 3D chromatin interactions often occurs coincidently with hypermethylation and loss of ER binding. Alterations in active A and inactive B chromosomal compartments are also associated with decreased ER binding and atypical interactions and gene expression. Together, our results suggest that 3D epigenome remodelling is a key mechanism underlying endocrine resistance in ER+ breast cancer.
Publisher: Cold Spring Harbor Laboratory
Date: 12-11-2021
DOI: 10.1101/2021.11.11.467877
Abstract: Neurons live for the lifespan of the in idual 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.
No related grants have been discovered for Katherine Giles.