AP-1 Transcription Factors and the BAF Complex Mediate Signal-Dependent Enhancer Selection

Vierbuchen, Thomas; Ling, Emi; Cowley, Christopher; Couch, Cameron H.; Wang, Xiaofeng; Harmin, David A.; Roberts, Charles W.M.; Greenberg, Michael E.

doi:10.1016/j.molcel.2017.11.026

Cited by 371 publications

(388 citation statements)

References 70 publications

(92 reference statements)

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“…We also performed ChIP-seq for the components of the BAF chromatin-remodeling complex and observed attenuated occupancy of BRG1 and ARID1B on the GAIN sites ( Figure 5D). This is consistent with a recent report that AP1 can mediate signal-dependent enhancer selection by recruiting the BAF complex to establish accessible chromatin 46 . The effects of JUN KD on GAIN enhancer landscape were exemplified at the EGFR or CXCL8 gene loci ( Figure 5E).…”

Section: Ap1-mediated Gain Enhancer Activation Promotes Hormone Resissupporting

confidence: 93%

Coordinate Enhancer Reprogramming by GATA3 and AP1 Promotes Phenotypic Plasticity to Achieve Breast Cancer Endocrine Resistance

Zhang

Xue

et al. 2019

Preprint

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Acquired therapy resistance is a major problem for anticancer treatment, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model for endocrine resistance, we show that hormone resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Our extensive omics studies, including GRO-seq on enhancer landscapes, demonstrate that the global enhancer gain/loss reprogramming driven by the differential interactions between ERα and other oncogenic transcription factors (TFs), predominantly GATA3 and AP1, profoundly alters breast cancer transcriptional programs. Our functional studies in multiple biological systems including culture and xenograft models of MCF7 and T47D lines support a coordinate role of GATA3 and AP1 in enhancer reprogramming that promotes phenotypic plasticity and endocrine resistance. Collectively, our study implicates that changes in TF-TF and TF-enhancer interactions can lead to genome-wide enhancer reprogramming, resulting in transcriptional dysregulations that promote plasticity and cancer therapy-resistance progression.However, when patients with ERα-positive breast cancer receive endocrine therapies for a period of 5 years, more than 30% of these patients eventually develop resistance and disease recurrence 9, 10 . As loss of ERα expression during therapies or metastatic progression is only found in ≤10% of patients 9 , this hormone-receptor pathway remains a major research focus for additional targeted therapies.Substantial evidence suggests that changes of components along the ERα axis, such as mutations or altered expression of ERα itself or ERα-interacting cofactors, may reprogram the ERα-mediated transcriptome that underlie the development of endocrine resistance [11][12][13] . Differential ERα binding is 5 also associated with clinical breast cancer progression 14 . However, the underlying molecular mechanisms of transcriptome transitions mediated by ERα during breast cancer progression and endocrine resistance are not well known.Enhancers are important distal DNA regulatory elements that control temporal-or spatial-specific gene expression patterns during development and other biological processes [15][16][17] . Dysregulation of enhancer function is involved in many diseases, particularly in cancers. Our previous genome-wide ChIP-seq studies have revealed that E 2 /ERα regulates its target gene expression program primarily through binding at distal enhancers to dictate cell growth and endocrine response 18,19 . Emerging evidence has implicated the link of epigenetic alterations of ERα-bound enhancers to hormone resistance and cancer invasion 14,20 . Thus, investigating oncogenic mechanisms that lead to the alterations of the ERα cistrome is critical for both understanding cancer progression and identifying of potential new cancer therapies.In this study, we compared matched control and resistant cells lin...

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Section: Ap1-mediated Gain Enhancer Activation Promotes Hormone Resissupporting

confidence: 93%

Coordinate Enhancer Reprogramming by GATA3 and AP1 Promotes Phenotypic Plasticity to Achieve Breast Cancer Endocrine Resistance

Zhang

Xue

et al. 2019

Preprint

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“…As the region around peak B has active enhancer marks, we conclude that MITF signaling is induced by activity and regulates an enhancer region in an intron of Kcnd3 leading to an activity-dependent increase in Kcnd3 expression in projection neurons of the OB. In accordance with this, stimulus dependent enhancer activity has previously been described in neurons [10,[40][41][42][43].…”

Section: Activity-dependent Increase In Kcnd3 Expression Requires Mitsupporting

confidence: 81%

Mitf links neuronal activity and long-term homeostatic intrinsic plasticity

Atacho

Reynisson

Pétursdóttir

et al. 2018

Preprint

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“…In particular, SMARCD1 was shown to be AP-1 interacting partner in yeast two-hybrid screen (Ito et al, 2001). ATF3 was shown to physically interact with SMARCA4 (BRG1-ATPase) (Xu et al, 2011), while a more recent study showed interaction of FOS with 10 out of 15 BAF members and ability of other FOS family members (FOSD, FOSL1/2) to recruit both SMARCB1 and SMARCD1 (Vierbuchen et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Co-Stimulation–Induced AP-1 Activity is Required for Chromatin Opening During T Cell Activation

Yukawa

Jagannathan

Kartashov

et al. 2019

Preprint

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Activation of T cells is dependent on organized and timely opening and closing of chromatin. Herein, we identify AP-1 as the transcription factor that directs most of this remodeling. Chromatin accessibility profiling showed quick opening of closed chromatin in naïve T cells within 5 hours of activation. These newly open regions were strongly enriched for the AP-1 motif, and indeed, ChIP-seq demonstrated AP-1 binding at more than 70% of them. Broad inhibition of AP-1 activity prevented chromatin opening at AP-1 sites and reduced expression of nearby genes. Similarly, induction of anergy in the absence of costimulation during activation, was associated with reduced induction of AP-1 and a failure of proper chromatin remodeling. The translational relevance of these findings was highlighted by the substantial overlap of AP-1-dependent elements with risk loci for multiple immune diseases, including multiple sclerosis, inflammatory bowel disease and allergic disease. Our findings define AP-1 as the key link between T cell activation and chromatin remodeling.

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AP-1 Transcription Factors and the BAF Complex Mediate Signal-Dependent Enhancer Selection

Cited by 371 publications

References 70 publications

Coordinate Enhancer Reprogramming by GATA3 and AP1 Promotes Phenotypic Plasticity to Achieve Breast Cancer Endocrine Resistance

Coordinate Enhancer Reprogramming by GATA3 and AP1 Promotes Phenotypic Plasticity to Achieve Breast Cancer Endocrine Resistance

Mitf links neuronal activity and long-term homeostatic intrinsic plasticity

Co-Stimulation–Induced AP-1 Activity is Required for Chromatin Opening During T Cell Activation

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