scholarly journals Integrative analysis of histopathological images and chromatin accessibility data for estrogen receptor-positive breast cancer

2020 ◽  
Vol 13 (S11) ◽  
Author(s):  
Siwen Xu ◽  
Zixiao Lu ◽  
Wei Shao ◽  
Christina Y. Yu ◽  
Jill L. Reiter ◽  
...  
Keyword(s):  
Canonical Correlation ◽  
Target Genes ◽  
Chromatin Accessibility ◽  
Integrative Analysis ◽  
Epithelial Tissue ◽  
Regulatory Regions ◽  
Potential Target ◽  
Histopathological Images ◽  
Tissue Proportion ◽  
Positive Breast Cancer

Abstract Background Existing studies have demonstrated that the integrative analysis of histopathological images and genomic data can be used to better understand the onset and progression of many diseases, as well as identify new diagnostic and prognostic biomarkers. However, since the development of pathological phenotypes are influenced by a variety of complex biological processes, complete understanding of the underlying gene regulatory mechanisms for the cell and tissue morphology is still a challenge. In this study, we explored the relationship between the chromatin accessibility changes and the epithelial tissue proportion in histopathological images of estrogen receptor (ER) positive breast cancer. Methods An established whole slide image processing pipeline based on deep learning was used to perform global segmentation of epithelial and stromal tissues. We then used canonical correlation analysis to detect the epithelial tissue proportion-associated regulatory regions. By integrating ATAC-seq data with matched RNA-seq data, we found the potential target genes that associated with these regulatory regions. Then we used these genes to perform the following pathway and survival analysis. Results Using canonical correlation analysis, we detected 436 potential regulatory regions that exhibited significant correlation between quantitative chromatin accessibility changes and the epithelial tissue proportion in tumors from 54 patients (FDR < 0.05). We then found that these 436 regulatory regions were associated with 74 potential target genes. After functional enrichment analysis, we observed that these potential target genes were enriched in cancer-associated pathways. We further demonstrated that using the gene expression signals and the epithelial tissue proportion extracted from this integration framework could stratify patient prognoses more accurately, outperforming predictions based on only omics or image features. Conclusion This integrative analysis is a useful strategy for identifying potential regulatory regions in the human genome that are associated with tumor tissue quantification. This study will enable efficient prioritization of genomic regulatory regions identified by ATAC-seq data for further studies to validate their causal regulatory function. Ultimately, identifying epithelial tissue proportion-associated regulatory regions will further our understanding of the underlying molecular mechanisms of disease and inform the development of potential therapeutic targets.

scholarly journals Chromatin-directed proteomics-identified network of endogenous androgen receptor in prostate cancer cells

Oncogene ◽  
2021 ◽  
Author(s):  
Kaisa-Mari Launonen ◽  
Ville Paakinaho ◽  
Gianluca Sigismondo ◽  
Marjo Malinen ◽  
Reijo Sironen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Protein A ◽  
Chorioallantoic Membrane ◽  
Chromatin Accessibility ◽  
Castration Resistant Prostate Cancer ◽  
Novel Therapy ◽  
Mesenchymal Transition

AbstractTreatment of prostate cancer confronts resistance to androgen receptor (AR)-targeted therapies. AR-associated coregulators and chromatin proteins hold a great potential for novel therapy targets. Here, we employed a powerful chromatin-directed proteomics approach termed ChIP-SICAP to uncover the composition of chromatin protein network, the chromatome, around endogenous AR in castration resistant prostate cancer (CRPC) cells. In addition to several expected AR coregulators, the chromatome contained many nuclear proteins not previously associated with the AR. In the context of androgen signaling in CRPC cells, we further investigated the role of a known AR-associated protein, a chromatin remodeler SMARCA4 and that of SIM2, a transcription factor without a previous association with AR. To understand their role in chromatin accessibility and AR target gene expression, we integrated data from ChIP-seq, RNA-seq, ATAC-seq and functional experiments. Despite the wide co-occurrence of SMARCA4 and AR on chromatin, depletion of SMARCA4 influenced chromatin accessibility and expression of a restricted set of AR target genes, especially those involved in cell morphogenetic changes in epithelial-mesenchymal transition. The depletion also inhibited the CRPC cell growth, validating SMARCA4’s functional role in CRPC cells. Although silencing of SIM2 reduced chromatin accessibility similarly, it affected the expression of a much larger group of androgen-regulated genes, including those involved in cellular responses to external stimuli and steroid hormone stimulus. The silencing also reduced proliferation of CRPC cells and tumor size in chick embryo chorioallantoic membrane assay, further emphasizing the importance of SIM2 in CRPC cells and pointing to the functional relevance of this potential prostate cancer biomarker in CRPC cells. Overall, the chromatome of AR identified in this work is an important resource for the field focusing on this important drug target.

scholarly journals High-throughput single-cell chromatin accessibility CRISPR screens enable unbiased identification of regulatory networks in cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sarah E. Pierce ◽  
Jeffrey M. Granja ◽  
William J. Greenleaf
Keyword(s):  
Transcription Factor ◽  
Single Cell ◽  
Cancer Cells ◽  
High Throughput ◽  
Regulatory Networks ◽  
Temporal Dynamics ◽  
Chromatin Accessibility ◽  
Regulatory Regions ◽  
Factor Binding ◽  
Genome Wide

AbstractChromatin accessibility profiling can identify putative regulatory regions genome wide; however, pooled single-cell methods for assessing the effects of regulatory perturbations on accessibility are limited. Here, we report a modified droplet-based single-cell ATAC-seq protocol for perturbing and evaluating dynamic single-cell epigenetic states. This method (Spear-ATAC) enables simultaneous read-out of chromatin accessibility profiles and integrated sgRNA spacer sequences from thousands of individual cells at once. Spear-ATAC profiling of 104,592 cells representing 414 sgRNA knock-down populations reveals the temporal dynamics of epigenetic responses to regulatory perturbations in cancer cells and the associations between transcription factor binding profiles.

scholarly journals Epigenetic Influences in the Aetiology of Cancers Arising from Breast and Prostate: A Hypothesised Transgenerational Evolution in Chromatin Accessibility

ISRN Oncology ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Francis L. Martin
Keyword(s):  
Target Genes ◽  
Epigenetic Modification ◽  
Intervention Strategy ◽  
Epidemiological Studies ◽  
Chromatin Accessibility ◽  
Dietary Factors ◽  
Heterocyclic Aromatic Amines ◽  
Tumour Suppressor Genes ◽  
Multistage Model ◽  
Migrant Populations

Epidemiological studies have consistently supported the notion that environmental and/or dietary factors play a central role in the aetiology of cancers of the breast and prostate. However, for more than five decades investigators have failed to identify a single cause-and-effect factor, which could be implicated; identification of a causative entity would allow the implementation of an intervention strategy in at-risk populations. This suggests a more complex pathoaetiology for these cancer sites, compared to others. When one examines the increases or decreases in incidence of specific cancers amongst migrant populations, it is notable that disease arising in colon or stomach requires one or at most two generations to exhibit a change in incidence to match that of high-incidence regions, whereas for breast or prostate cancer, at least three generations are required. This generational threshold could suggest a requirement for nonmutation-driven epigenetic alterations in the F0/F1 generations (parental/offspring adopting a more westernized lifestyle), which then predisposes the inherited genome of subsequent generations to mutagenic/genotoxic alterations leading to the development of sporadic cancer in these target sites. As such, individual susceptibility to carcinogen insult would not be based per se on polymorphisms in activating/detoxifying/repair enzymes, but on elevated accessibility of crucial target genes (e.g., oncogenes, tumour suppressor genes) or hotspots therein to mutation events. This could be termed a genomic susceptibility organizational structure (SOS). Several exposures including alcohol and heavy metals are epigens (i.e., modifiers of the epigenome), whereas others are mutagenic/genotoxic, for example, heterocyclic aromatic amines; humans are continuously and variously exposed to mixtures of these agents. Within such a transgenerational multistage model of cancer development, determining the interaction between epigenetic modification to generate a genomic SOS and genotoxic insult will facilitate a new level of understanding in the aetiology of cancer.

scholarly journals ASC proneural transcription factors mediate the timely initiation of the neural program during neuroectodermal to neuroblast transition ensuring progeny fidelity

2021 ◽  
Author(s):  
Vasiliki Theodorou ◽  
Aikaterini Stefanaki ◽  
Minas Drakos ◽  
Dafne Triantafyllou ◽  
Christos Delidakis
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Cis Elements ◽  
Enhancer Activity ◽  
Timely Initiation ◽  
Chromatin Dynamics ◽  
Neural Fate ◽  
Neural Specification

Background: ASC/ASCL proneural transcription factors are oncogenic and exhibit impressive reprogramming and pioneer activities. In both Drosophila and mammals, these factors are central in the early specification of the neural fate, where they act in opposition to Notch signalling. However, the role of ASC on the chromatin during CNS neural stem cells birth remains elusive. Results: We investigated the chromatin changes accompanying neural commitment using an integrative genetics and genomics methodology. We found that ASC factors bind equally strongly to two distinct classes of cis-regulatory elements: open regions remodeled earlier during maternal to zygotic transition by Zelda and Zelda-independent, less accessible regions. Both classes cis-elements exhibit enhanced chromatin accessibility during neural specification and correlate with transcriptional regulation of genes involved in many biological processes necessary for neuroblast function. We identified an ASC-Notch regulated TF network that most likely act as the prime regulators of neuroblast function. Using a cohort of ASC target genes, we report that ASC null neuroblasts are defectively specified, remaining initially stalled, lacking expression of many proneural targets and unable to divide. When they eventually start proliferating, they produce compromised progeny. Generation of lacZ reporter lines driven by proneural-bound elements display enhancer activity within neuroblasts and proneural dependency. Therefore, the partial neuroblast identity seen in the absence of ASC genes is driven by other, proneural-independent, cis-elements. Neuroblast impairment and the late differentiation defects of ASC mutants are corrected by ectodermal induction of individual ASC genes but not by individual members of the TF network downstream of ASC. However, in wild type embryos induction of individual members of this network induces CNS hyperplasia, suggesting that they synergize with the activating function of ASC to establish the chromatin dynamics that promote neural specification. Conclusion: ASC factors bind a large number of enhancers to orchestrate the timely activation of the neural chromatin program during neuroectodermal to neuroblast transition. This early chromatin remodeling is crucial for both neuroblast homeostasis as well as future progeny fidelity.

scholarly journals Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to Oesophageal Adenocarcinoma

2020 ◽  
Author(s):  
Connor Rogerson ◽  
Samuel Ogden ◽  
Edward Britton ◽  
Yeng Ang ◽  
Andrew D. Sharrocks ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Prognostic Significance ◽  
Gene Expression Signature ◽  
Chromatin Accessibility ◽  
Oesophageal Adenocarcinoma ◽  
Cell Cycle Gene ◽  
A Cell

AbstractOesophageal adenocarcinoma (OAC) is one of the most common causes of cancer deaths and yet compared to other common cancers, we know relatively little about the underlying molecular mechanisms. Barrett’s oesophagus (BO) is the only known precancerous precursor to OAC, but our understanding about the specific events leading to OAC development is limited. Here, we have integrated gene expression and chromatin accessibility profiles of human biopsies of BO and OAC and identified a strong cell cycle gene expression signature in OAC compared to BO. Through analysing associated chromatin accessibility changes, we have implicated the transcription factor KLF5 in the transition from BO to OAC. Importantly, we show that KLF5 expression is unchanged during this transition, but instead, KLF5 is redistributed across chromatin in OAC cells to directly regulate cell cycle genes specifically in OAC. Our findings have potential prognostic significance as the survival of patients with high expression of KLF5 target genes is significantly lower. We have provided new insights into the gene expression networks in OAC and the mechanisms behind progression to OAC, chiefly the repurposing of KLF5 for novel regulatory activity in OAC.

scholarly journals Identification of potential target genes of USP22 via ChIP-seq and RNA-seq analysis in HeLa cells

2018 ◽  
Vol 41 (2) ◽  
pp. 488-495 ◽  
Author(s):  
Zhen Gong ◽  
Jianyun Liu ◽  
Xin Xie ◽  
Xiaoyuan Xu ◽  
Ping Wu ◽  
...  
Keyword(s):  
Hela Cells ◽  
Target Genes ◽  
Rna Seq ◽  
Potential Target

scholarly journals Genome-wide effects of chromatin on vitamin D signaling

2020 ◽  
Vol 64 (4) ◽  
pp. R45-R56 ◽  
Author(s):  
Andrea Hanel ◽  
Henna-Riikka Malmberg ◽  
Carsten Carlberg
Keyword(s):  
Vitamin D ◽  
Binding Sites ◽  
Target Genes ◽  
Chromatin Accessibility ◽  
Transcription Start Sites ◽  
Dihydroxyvitamin D ◽  
Genome Wide ◽  
Spatio Temporal ◽  
Vitamin D Signaling ◽  
The Impact

Molecular endocrinology of vitamin D is based on the activation of the transcription factor vitamin D receptor (VDR) by the vitamin D metabolite 1α,25-dihydroxyvitamin D3. This nuclear vitamin D-sensing process causes epigenome-wide effects, such as changes in chromatin accessibility as well as in the contact of VDR and its supporting pioneer factors with thousands of genomic binding sites, referred to as vitamin D response elements. VDR binding enhancer regions loop to transcription start sites of hundreds of vitamin D target genes resulting in changes of their expression. Thus, vitamin D signaling is based on epigenome- and transcriptome-wide shifts in VDR-expressing tissues. Monocytes are the most responsive cell type of the immune system and serve as a paradigm for uncovering the chromatin model of vitamin D signaling. In this review, an alternative approach for selecting vitamin D target genes is presented, which are most relevant for understanding the impact of vitamin D endocrinology on innate immunity. Different scenarios of the regulation of primary upregulated vitamin D target genes are presented, in which vitamin D-driven super-enhancers comprise a cluster of persistent (constant) and/or inducible (transient) VDR-binding sites. In conclusion, the spatio-temporal VDR binding in the context of chromatin is most critical for the regulation of vitamin D target genes.

Elevation of MicroRNA-126 Levels in Intracranial Aneurysm and Bioinformatic Analysis of Potential Molecular Mechanisms

2021 ◽  
Vol 11 (4) ◽  
pp. 573-579
Author(s):  
Pan Huang ◽  
Min Xu ◽  
Xiao-Ying He
Keyword(s):  
Intracranial Aneurysm ◽  
Peripheral Blood ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Kegg Pathway ◽  
Bioinformatic Analysis ◽  
Control Group ◽  
Potential Target ◽  
Fas Signaling

The study is to investigation of microRNA-126 levels in patients with intracranial aneurysm and bioinformatic analysis of the molecular mechanisms involved. A total of 166 patients with ICA who were hospitalized or examined in our hospital from September 2015 to December 2017 were used as the experimental group (ICA group). This group included 120 patients with unruptured intracranial aneurysm (UICA; UICA group) and 46 patients with ruptured intracranial aneurysm (RICA); RICA group). The UICA group was further subdivided into 42 surgical groups (S group) and 78 nonsurgical groups (NS group). Sixty-three normal people without intracranial aneurysms were selected as the control group. RT-PCR was used to quantitatively detect the relative expression of microRNA- 126 in peripheral blood mononuclear cells at the time of admission and immediately after surgery. The UCSC database was used to analyze the gene locus and homology of microRNA-126. The TargetScan database and CoMeTa database were used to predict the potential target genes of microRNA-126. The DAVID database was used to enrich the function of potential target genes of microRNA-126 (GO enrichment) and KEGG pathway enrichment for analysis. The expression level of microRNA-126 in peripheral blood was significantly higher in the ICA group than in the control group (P <0.01), significantly higher in the RICA group than in the UICA group (P <0.05). Expression was also higher in the NS group than in the S group but the difference was nonsignificant (P >0.05). A total of 15 potential target genes including ITGA6, CRK, PCDH7, and ADAM9 were identified through the target gene prediction software and GO analysis and KEGG pathway analysis showed that the function of the microRNA-126 target gene was mainly focused on protein binding and the FAS signaling pathway. In Conclusion the microRNA-126 is up-regulated in ICA patients and affects ICA by regulating multiple target genes in the FAS signaling pathway.

Calcineurin regulates the stability and activity of estrogen receptor α

2021 ◽  
Vol 118 (44) ◽  
pp. e2114258118
Author(s):  
Takahiro Masaki ◽  
Makoto Habara ◽  
Yuki Sato ◽  
Takahiro Goshima ◽  
Keisuke Maeda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
The Stability ◽  
Positive Breast Cancer

Estrogen receptor α (ER-α) mediates estrogen-dependent cancer progression and is expressed in most breast cancer cells. However, the molecular mechanisms underlying the regulation of the cellular abundance and activity of ER-α remain unclear. We here show that the protein phosphatase calcineurin regulates both ER-α stability and activity in human breast cancer cells. Calcineurin depletion or inhibition down-regulated the abundance of ER-α by promoting its polyubiquitination and degradation. Calcineurin inhibition also promoted the binding of ER-α to the E3 ubiquitin ligase E6AP, and calcineurin mediated the dephosphorylation of ER-α at Ser294 in vitro. Moreover, the ER-α (S294A) mutant was more stable and activated the expression of ER-α target genes to a greater extent compared with the wild-type protein, whereas the extents of its interaction with E6AP and polyubiquitination were attenuated. These results suggest that the phosphorylation of ER-α at Ser294 promotes its binding to E6AP and consequent degradation. Calcineurin was also found to be required for the phosphorylation of ER-α at Ser118 by mechanistic target of rapamycin complex 1 and the consequent activation of ER-α in response to β-estradiol treatment. Our study thus indicates that calcineurin controls both the stability and activity of ER-α by regulating its phosphorylation at Ser294 and Ser118. Finally, the expression of the calcineurin A–α gene (PPP3CA) was associated with poor prognosis in ER-α–positive breast cancer patients treated with tamoxifen or other endocrine therapeutic agents. Calcineurin is thus a promising target for the development of therapies for ER-α–positive breast cancer.

Integrative chemo-immune-radiological treatment of HER2 positive breast cancer combined with a review of potential microRNAs involved and analysis of experimental results from sub-THz vibrational spectroscopy

2021 ◽  
Vol 6 (12) ◽  
Keyword(s):  
Breast Cancer ◽  
Vibrational Spectroscopy ◽  
Radiation Treatment ◽  
Integrative Analysis ◽  
Micro Rna ◽  
Thz Spectroscopy ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Spectroscopic Signatures ◽  
Positive Breast Cancer

In this paper we present the results of a Breast Cancer study by integrative analysis of a NIH approved treatment for HER2 positive breast cancer. This study is combined with analysis of Micro-RNA involvement from application of sub-THz spectroscopy for visualization of molecules circulating in blood by measuring saliva. The combination of Taxol-Generic Name-Paclitaxel (PT-J9267) and Trastuzumab-ANNS 0/0 and KadcylaTM (Genetic Name Ado-Trastuzumab Emtansine) were used in 3-stages of combined chemotherapeutic and immune-treatments followed by Radiation treatment. The goal of using PT was to stop spread of the disease to other organs outside of the breast and under arm lymph nodes, as well as to shrink the size of the tumor to facilitate surgery and radiology in continuation of the treatment. Trastuzumab (TZ) was added to PT in the 2nd step to prevent the development of chemoresistance. Intravenous infusion of Kadcyla was used mainly to prevent metastasis. Integrative analysis of microRNA participation was conducted based on literature review and sub-Terahertz vibrational spectroscopy measurements of absorption spectra from samples taken weekly before and after each treatment, using Vibratess’ spectrometer. The results from sub-THz spectroscopy in this work demonstrate dramatical modification of spectroscopic signatures from patient samples following disease development and the initial steps in the course of treatment. These changes reflect the deep global regulation (reduction) of the initially participating microRNAs amounts and changes in the microRNAs contributing to the spectra.

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