An integrative transcriptomics approach identifies miR-503 as a candidate master regulator of the estrogen response in MCF-7 breast cancer cells

Baran-Gale, Jeanette; Purvis, Jeremy E.; Sethupathy, Praveen

doi:10.1261/rna.056895.116

Cited by 41 publications

(33 citation statements)

References 60 publications

(93 reference statements)

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“…Conversely, the genes that are away from clustered enhancers but closer to random ERα sites did not show E2-dependent induction. Even though the level of nascent transcripts drop at 3h post-E2, mRNAs levels exhibit such a drop between 3-4h post-E2 as observed in a publicly available time-course mRNA-seq upon E2 addition [25] (S10B Fig).…”

Section: Emergence Of Ldecs Is Correlated With Robust Target Gene Expmentioning

confidence: 71%

Ligand dependent gene regulation by transient ERα clustered enhancers

et al. 2020

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Unliganded Estrogen receptor alpha (ERα) has been implicated in ligand-dependent gene regulation. Upon ligand exposure, ERα binds to several EREs relatively proximal to the premarked, unliganded ERα-bound sites and affects transient but robust gene expression. However, the underlying mechanisms are not fully understood. Here we demonstrate that upon ligand stimulation, persistent sites interact extensively, via chromatin looping, with the proximal transiently ERα-bound sites, forming Ligand Dependent ERα Enhancer Cluster in 3D (LDEC). The E2-target genes are regulated by these clustered enhancers but not by the H3K27Ac super-enhancers. Further, CRISPR-based deletion of TFF1 persistent site disrupts the formation of its LDEC resulting in the loss of E2-dependent expression of TFF1 and its neighboring genes within the same TAD. The LDEC overlap with nuclear ERα condensates that coalesce in a ligand and persistent site dependent manner. Furthermore, formation of clustered enhancers, as well as condensates, coincide with the active phase of signaling and their later disappearance results in the loss of gene expression even though persistent sites remain bound by ERα. Our results establish, at TFF1 and NRIP1 locus, a direct link between ERα condensates, ERα enhancer clusters, and transient, but robust, gene expression in a ligand-dependent fashion. Author summaryERα occupies its cognate binding sites on the genome, upon estrogen stimulation, to bring about the signaling mediated response. However, ERα has been implicated in gene regulation even in the absence of hormone and its underlying mechanisms are not known. Here we show that, unliganded ERα-bound genomic sites are necessary for the emergence of active enhancers upon estrogen stimulation. Several ERα sites emerge in proximity to these unliganded ERα sites which loop with each other in three-dimensional nuclear space forming the enhancer:ERα clusters that we call Ligand dependent enhancer PLOS Genetics | https://doi.

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Section: Emergence Of Ldecs Is Correlated With Robust Target Gene Expmentioning

confidence: 71%

Ligand dependent gene regulation by transient ERα clustered enhancers

et al. 2020

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“…2. To do so, we considered temporal gene expression data from MCF7 breast cancer cells and LNCaP prostate cancer cells in response to estradiol and dihydrotestosterone (DHT, androgen) treatment (SRA accession #: SRP070657 and SRP059762) 40 . Notably, we observed that in human post-mortem lungs, genes with expression patterns that most strongly correlate with TMPRSS2 also behave similarly to TMPRSS2 in response to estradiol and DHT treatment in MCF7 and LNCaP cells, respectively (Fig.…”

Section: Relevance In Lung Tissue Of Estradiol-based Transcriptional mentioning

confidence: 99%

Transcriptional Inhibition of Host Viral Entry Proteins as a Therapeutic Strategy for SARS-CoV-2

Wang¹,

Dhindsa²,

Povysil³

et al. 2020

Preprint

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There is an urgent need to identify effective therapies for COVID-19 given that a broadly available and effective vaccine is likely at least one year away. Here, we identify compounds that transcriptionally inhibit host proteins required for SARS-CoV-2 entry and should be evaluated for efficacy in SARS-CoV-2 viral infection assays. Recognizing the need for immediately available treatment options, we focused particular attention on FDA-approved drugs that could be immediately repurposed to treat COVID-19 patients. By mining publicly available gene expression data, we identify several compounds that down-regulate TMPRSS2, a protein required for SARS-CoV-2 entry that has emerged as a promising therapeutic target. Among these, we find twenty independent studies that implicate estrogen-related and androgen-related compounds as transcriptional modulators of TMPRSS2 expression, suggesting that these drugs and others acting on the pathway may be promising therapeutic candidates for COVID-19 for further testing. It is also noteworthy that TMPRSS2 has highly variable and skewed expression in humans, spanning two orders of magnitude with a small minority of individuals having extremely high expression. Combined with literature showing that TMPRSS2 loss-of-function in mouse is protective against SARS while anti-estrogen treatment predicted to increase TMPRSS2 expression exacerbates SARS, this observation raises the hypothesis that TMPRSS2 expression may positively correlate with severity in COVID-19.

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“…99 Thus, it is not clear yet why women are less susceptible to COVID-19 infections if the expression of ACE2 is greater in the lung tissue. For example, estrogen and androgen compounds reduce TMPRSS2 levels in MCF-7 cells, 102 suggesting its potential role of steroid hormones in COVID-19 therapeutic strategy.…”

Section: Ace2 and Estrogen Interactionmentioning

confidence: 99%

SARS‐CoV‐2 and the possible connection to ERs, ACE2, and RAGE: Focus on susceptibility factors

et al. 2020

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has provoked major stresses on the health-care systems of several countries, and caused the death of more than a quarter of a million people globally, mainly in the elderly population with preexisting pathologies. Previous studies with coronavirus (SARS-CoV) point to gender differences in infection and disease progression with increased susceptibility in male patients, indicating that estrogens may be associated with physiological protection against the coronavirus. Therefore, the objectives of this work are threefold. First, we aim to summarize the SARS-CoV-2 infection pathway and the roles both the virus and patient play in COVID-19 (Coronavirus disease 2019) progression, clinical symptomatology, and mortality. Second, we detail the effect estrogen has on viral infection and host infection response, including its role in both the regulation of key viral receptor expression and the mediation of inflammatory activity. Finally, we describe how ERs (estrogen receptors) and RAGE (receptor for advanced glycation end-products) play a critical role in metabolic pathways, which we 14104 | STILHANO eT AL. 1 | INTRODUCTION 1.1 | SARS-CoV-2 and COVID-19 Coronavirus disease 2019 (COVID-19) is a disease caused by the new coronavirus called SARS-CoV-2 (SARScoronavirus 2). In December 2019, the first case of COVID-19 was diagnosed in the city of Wuhan, China. 1 The virus disseminated rapidly and the World Health Organization (WHO) declared SARS-CoV-2 as a pandemic on March 11th 2020, given that it had already spread to more than 188 countries on five continents. Updated epidemiological data from the Johns Hopkins University indicator shows that there are more than 20 million cases and over 730 thousand deaths due to COVID-19 by the beginning of August 2020 (https://coron avirus.jhu.edu/map.html-accessed on August 11, 2020 14:00 GMT). The Case Fatality Rate (CFR) for COVID-19 increases exponentially with age. 2,3 For example, for patients aged between 65 and 74 years old, the CFR is 3%-5%, 4%-11% CFR for 75 and 84 years old and 10%-27% CFR for the patients above 85 years old. 2 Obesity, diabetes, and hypertension are comorbidities associated with increased risk for developing the severe form of COVID-19. Data attributed to the Centers for Disease Control and Prevention (https://www.cdc.gov/coron aviru s/2019-ncov/need-extra preca ution s/group sat -highe r-risk. html) shows that diabetes is one of the major risk factors for fatal outcomes from COVID-19. Considering that diabetic patients usually have hyperglycemia, impaired immune function, and several comorbidities such as hypertension, dyslipidemia, and cardiovascular disease, this group is more susceptible to be severely infected by SARS-CoV-2. 4 Another important risk for fatal COVID-19 is obesity, particularly in males. 5,6 Moreover, COVID-19 also affects more severely individuals with metabolic syndrome, probably because these patients have a pro-inflammatory condition that may contribute to enhance...

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An integrative transcriptomics approach identifies miR-503 as a candidate master regulator of the estrogen response in MCF-7 breast cancer cells

Cited by 41 publications

References 60 publications

Ligand dependent gene regulation by transient ERα clustered enhancers

Ligand dependent gene regulation by transient ERα clustered enhancers

Transcriptional Inhibition of Host Viral Entry Proteins as a Therapeutic Strategy for SARS-CoV-2

SARS‐CoV‐2 and the possible connection to ERs, ACE2, and RAGE: Focus on susceptibility factors

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