FOXD3 controls pluripotency through modulating enhancer activity

Abstract The glucocorticoid (GR) and androgen (AR) receptors execute unique functions in vivo, yet have nearly identical DNA binding specificities. To identify mechanisms that facilitate functional diversification among these transcription factor paralogs, we studied them in an equivalent cellular context. Analysis of chromatin and sequence suggest that divergent binding, and corresponding gene regulation, are driven by different abilities of AR and GR to interact with relatively inaccessible chromatin. Divergent genomic binding patterns can also be the result of subtle differences in DNA binding preference between AR and GR. Furthermore, the sequence composition of large regions (>10 kb) surrounding selectively occupied binding sites differs significantly, indicating a role for the sequence environment in guiding AR and GR to distinct binding sites. The comparison of binding sites that are shared shows that the specificity paradox can also be resolved by differences in the events that occur downstream of receptor binding. Specifically, shared binding sites display receptor-specific enhancer activity, cofactor recruitment and changes in histone modifications. Genomic deletion of shared binding sites demonstrates their contribution to directing receptor-specific gene regulation. Together, these data suggest that differences in genomic occupancy as well as divergence in the events that occur downstream of receptor binding direct functional diversification among transcription factor paralogs.

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A Functional Variant on 9p21.3 Related to Glioma Risk Affects Enhancer Activity and Modulates Expression of CDKN2B‐AS1

Human Mutation ◽

10.1002/humu.24244 ◽

2021 ◽

Author(s):

Mourad Wagdy Ali ◽

C. Pawan K. Patro ◽

Matthew Devall ◽

Christopher H. Dampier ◽

Sarah J. Plummer ◽

...

Keyword(s):

Enhancer Activity ◽

Functional Variant ◽

Glioma Risk

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Inferring time series chromatin states for promoter-enhancer pairs based on Hi-C data

BMC Genomics ◽

10.1186/s12864-021-07373-z ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Henriette Miko ◽

Yunjiang Qiu ◽

Bjoern Gaertner ◽

Maike Sander ◽

Uwe Ohler

Keyword(s):

Time Series ◽

Histone Modifications ◽

Gene Activation ◽

Expectation Maximization Algorithm ◽

Chromatin State ◽

Open Chromatin ◽

Multiple Time ◽

Enhancer Activity ◽

Chromatin States ◽

Multiple Time Points

Abstract Background Co-localized combinations of histone modifications (“chromatin states”) have been shown to correlate with promoter and enhancer activity. Changes in chromatin states over multiple time points (“chromatin state trajectories”) have previously been analyzed at promoter and enhancers separately. With the advent of time series Hi-C data it is now possible to connect promoters and enhancers and to analyze chromatin state trajectories at promoter-enhancer pairs. Results We present TimelessFlex, a framework for investigating chromatin state trajectories at promoters and enhancers and at promoter-enhancer pairs based on Hi-C information. TimelessFlex extends our previous approach Timeless, a Bayesian network for clustering multiple histone modification data sets at promoter and enhancer feature regions. We utilize time series ATAC-seq data measuring open chromatin to define promoters and enhancer candidates. We developed an expectation-maximization algorithm to assign promoters and enhancers to each other based on Hi-C interactions and jointly cluster their feature regions into paired chromatin state trajectories. We find jointly clustered promoter-enhancer pairs showing the same activation patterns on both sides but with a stronger trend at the enhancer side. While the promoter side remains accessible across the time series, the enhancer side becomes dynamically more open towards the gene activation time point. Promoter cluster patterns show strong correlations with gene expression signals, whereas Hi-C signals get only slightly stronger towards activation. The code of the framework is available at https://github.com/henriettemiko/TimelessFlex. Conclusions TimelessFlex clusters time series histone modifications at promoter-enhancer pairs based on Hi-C and it can identify distinct chromatin states at promoter and enhancer feature regions and their changes over time.

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Functional mapping of androgen receptor enhancer activity

Genome Biology ◽

10.1186/s13059-021-02339-6 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Chia-Chi Flora Huang ◽

Shreyas Lingadahalli ◽

Tunc Morova ◽

Dogancan Ozturan ◽

Eugene Hu ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Binding Sites ◽

Gene Promoters ◽

Strongly Correlated ◽

Enhancer Activity ◽

Drive Gene Expression ◽

In Vitro Cell Lines ◽

Drive Gene

Abstract Background Androgen receptor (AR) is critical to the initiation, growth, and progression of prostate cancer. Once activated, the AR binds to cis-regulatory enhancer elements on DNA that drive gene expression. Yet, there are 10–100× more binding sites than differentially expressed genes. It is unclear how or if these excess binding sites impact gene transcription. Results To characterize the regulatory logic of AR-mediated transcription, we generated a locus-specific map of enhancer activity by functionally testing all common clinical AR binding sites with Self-Transcribing Active Regulatory Regions sequencing (STARRseq). Only 7% of AR binding sites displayed androgen-dependent enhancer activity. Instead, the vast majority of AR binding sites were either inactive or constitutively active enhancers. These annotations strongly correlated with enhancer-associated features of both in vitro cell lines and clinical prostate cancer samples. Evaluating the effect of each enhancer class on transcription, we found that AR-regulated enhancers frequently interact with promoters and form central chromosomal loops that are required for transcription. Somatic mutations of these critical AR-regulated enhancers often impact enhancer activity. Conclusions Using a functional map of AR enhancer activity, we demonstrated that AR-regulated enhancers act as a regulatory hub that increases interactions with other AR binding sites and gene promoters.

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Chromatin remodeling effects on enhancer activity

Cellular and Molecular Life Sciences ◽

10.1007/s00018-016-2184-3 ◽

2016 ◽

Vol 73 (15) ◽

pp. 2897-2910 ◽

Cited By ~ 18

Author(s):

Estela García-González ◽

Martín Escamilla-Del-Arenal ◽

Rodrigo Arzate-Mejía ◽

Félix Recillas-Targa

Keyword(s):

Chromatin Remodeling ◽

Enhancer Activity

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