TFAP2C- and p63-Dependent Networks Sequentially Rearrange Chromatin Landscapes to Drive Human Epidermal Lineage Commitment

Li, Lingjie; Wang, Yong; Torkelson, Jessica L.; Shankar, Gautam; Pattison, Jillian M.; Zhen, Hanson H.; Fang, Fengqin; Duren, Zhana; Xin, Jingxue; Gaddam, Sadhana; Melo, Sandra P.; Piekos, Samantha N.; Li, Jiang; Liaw, Eric J.; Chen, Lang; Li, Rui; Wernig, Marius; Wong, Wing Hung; Chang, Howard Y.; Oro, Anthony E.

doi:10.1016/j.stem.2018.12.012

Cited by 85 publications

(96 citation statements)

References 37 publications

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“…For instance, TFAP2C expression was significantly associated with lung relapses, consistent with a recent study [27]. TFAP2C is a pioneer factor that plays important roles in pluripotency and lineage differentiation [87,88]. Interestingly, TFAP2C has been considered to regulate luminal differentiation and its motif is enriched in luminal breast cancer cells [26,89].…”

Section: Discussionsupporting

confidence: 86%

Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain

et al. 2020

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Background: Few somatic mutations have been linked to breast cancer metastasis, whereas transcriptomic differences among primary tumors correlate with incidence of metastasis, especially to the lungs and brain. However, the epigenomic alterations and transcription factors (TFs) which underlie these alterations remain unclear. Methods: To identify these, we performed RNA-seq, Chromatin Immunoprecipitation and sequencing (ChIP-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) of the MDA-MB-231 cell line and its brain (BrM2) and lung (LM2) metastatic sub-populations. We incorporated ATAC-seq data from TCGA to assess metastatic open chromatin signatures, and gene expression data from human metastatic datasets to nominate transcription factor biomarkers. Results: Our integrated epigenomic analyses found that lung and brain metastatic cells exhibit both shared and distinctive signatures of active chromatin. Notably, metastatic sub-populations exhibit increased activation of both promoters and enhancers. We also integrated these data with chromosome conformation capture coupled with ChIP-seq (HiChIP) derived enhancer-promoter interactions to predict enhancer-controlled pathway alterations. We found that enhancer changes are associated with endothelial cell migration in LM2, and negative regulation of epithelial cell proliferation in BrM2. Promoter changes are associated with vasculature development in LM2 and homophilic cell adhesion in BrM2. Using ATAC-seq, we identified a metastasis open-chromatin signature that is elevated in basal-like and HER2-enriched breast cancer subtypes and associates with worse prognosis in human samples. We further uncovered TFs associated with the open chromatin landscapes of metastatic cells and whose expression correlates with risk for metastasis. While some of these TFs are associated with primary breast tumor subtypes, others more specifically correlate with lung or brain metastasis. Conclusions: We identify distinctive epigenomic properties of breast cancer cells that metastasize to the lung and brain. We also demonstrate that signatures of active chromatin sites are partially linked to human breast cancer subtypes with poor prognosis, and that specific TFs can independently distinguish lung and brain relapse.

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Section: Discussionsupporting

confidence: 86%

Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain

et al. 2020

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“…T he barrier function of the skin is heavily dependent on the balance between self-renewal and differentiation of its basal stem/progenitor cell population. Transitions between stemness and differentiation states are determined by transcriptional and epigenetic changes that shape the genomic landscape of epithelial cells, affecting the differential binding of transcriptional activators and repressors to genes that participate in stem cell-renewal and the initiation of terminal differentiation [1][2][3] . YAP1 and its paralog TAZ (WWTR1) are co-transcriptional regulators downstream of the Hippo pathway 4,5 that are essential for skin homeostasis and epithelial stem cell maintenance [6][7][8][9] .…”

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confidence: 99%

YAP1/TAZ-TEAD transcriptional networks maintain skin homeostasis by regulating cell proliferation and limiting KLF4 activity

et al. 2020

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The Hippo TEAD-transcriptional regulators YAP1 and TAZ are central for cell renewal and cancer growth; however, the specific downstream gene networks involved in their activity are not completely understood. Here we introduce TEADi, a genetically encoded inhibitor of the interaction of YAP1 and TAZ with TEAD, as a tool to characterize the transcriptional networks and biological effects regulated by TEAD transcription factors. Blockage of TEAD activity by TEADi in human keratinocytes and mouse skin leads to reduced proliferation and rapid activation of differentiation programs. Analysis of gene networks affected by TEADi and YAP1/TAZ knockdown identifies KLF4 as a central transcriptional node regulated by YAP1/ TAZ-TEAD in keratinocyte differentiation. Moreover, we show that TEAD and KLF4 can regulate the activity of each other, indicating that these factors are part of a transcriptional regulatory loop. Our study establishes TEADi as a resource for studying YAP1/TAZ-TEAD dependent effects.

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“…These molecular characteristics are suggestive of a relatively quiescent, primitive stem/progenitor cell state, a notion supported by its placement as the initial state in the epidermal lineage (this study), and its high expression of Col17a1, which encodes a marker of long-term epidermal stem cells that can outcompete other cells (Liu et al, 2019). The Col17a1 Hi state is enriched for genes such as Trp63, a master regulator of various aspects of epidermal development, including the initial specification from simple epithelia, promotion of stratification, proliferation, as well as terminal differentiation (Li et al, 2019;Mills et al, 1999;Pattison et al, 2018;Truong et al, 2006;Yang et al, 1999). The reduction of basal cells in the Col17a1 Hi state during wound re-epithelization implicates their mobilization in the case of increased demands for cellular outputs.…”

Section: Discussionmentioning

confidence: 75%

Defining epidermal basal cell states during skin homeostasis and wound healing using single-cell transcriptomics

Haensel¹,

Jin²,

Cinco³

et al. 2019

Preprint

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Our knowledge of transcriptional heterogeneities in epithelial stem/progenitor cell compartments is limited. Epidermal basal cells sustain cutaneous tissue maintenance and drive wound healing. Previous studies have probed basal cell heterogeneity in stem/progenitor potential, but a non-biased dissection of basal cell dynamics during differentiation is lacking. Using single-cell RNA-sequencing coupled with RNAScope and fluorescence lifetime imaging, we identify three non-proliferative and one proliferative basal cell transcriptional states in homeostatic skin that differ in metabolic preference and become spatially partitioned during wound re-epithelialization. Pseudotemporal trajectory and RNA velocity analyses produce a quasi-linear differentiation hierarchy where basal cells progress from Col17a1 high /Trp63 high state to early response state, proliferate at the juncture of these two states, or become growth arrested before differentiating into spinous cells. Wound healing induces plasticity manifested by dynamic basalspinous interconversions at multiple basal states. Our study provides a systematic view of epidermal cellular dynamics supporting a revised "hierarchical-lineage" model of homeostasis.

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TFAP2C- and p63-Dependent Networks Sequentially Rearrange Chromatin Landscapes to Drive Human Epidermal Lineage Commitment

Cited by 85 publications

References 37 publications

Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain

Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain

YAP1/TAZ-TEAD transcriptional networks maintain skin homeostasis by regulating cell proliferation and limiting KLF4 activity

Defining epidermal basal cell states during skin homeostasis and wound healing using single-cell transcriptomics

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