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实验室

11:00-12:00, Friday, August 10, 2018


Speaker: Yejing Ge, Ph.D.

Assistant Professor

University of Texas MD Anderson Cancer Center

Topic:  Functional genomics of the skin epithelia

Host:   Ting Han, Ph.D.

Abstract

Defined by golden standards of long-term self-renewal and multi-lineage differentiation, stem cells (SCs) come in different flavors. In mammals, adult SCs are essential units to orchestrate postnatal remodeling and repair damage. In contrast to steady state, SCs in coping with stress and challenges often expand their fates and embark on behaviors distinct from their homeostatic patterns, known as plasticity. While plasticity is essential for organismal survival, its derailed regulation poses disease vulnerability to individuals, especially those undergoing prolonged stress. Under these scenarios, SCs are subjected to functional exhaustion frequently observed in aging, or malignant transformation that occurs in cancer. Research in the Ge lab applies principle of developmental biology in order to understand molecular mechanisms underlying SC plasticity, and how its deregulation causes human diseases.

One of the key hypotheses we set out to address is this long postulated idea “cancer is a wound that never heals”. Parallels between wound repair and cancer have emerged in many contexts, begging questions in regards to their molecular origin and functional relevance. Mouse skin represents an excellent model to address these questions. Its stem cells (SCs) are well defined, abundant, and genetically tractable. The skin epithelium has two distinct lineages, hair follicle (HF) and interfollicular epidermis (Epd), each harboring their own resident SCs. HF-SCs reside in a region of the follicle known as the bulge, and during homeostasis, their role is to fuel the cyclical bouts of HF regeneration and hair growth. By contrast, Epd-SCs reside in the innermost basal layer of Epd, where they generate upward flux of differentiating cells that produces the skin’s barrier. Upon injury, both HF- and Epd-SCs close to the wound site mobilize toward it, re-epithelializing the wound bed and restoring the barrier. When acquiring oncogenic mutations, SCs from both lineages can participate in tumor initiation and progression, such as squamous cell carcinomas (SCCs), frequently occurring in the skin. Studying skin SCCs, we found SCs adopt a plastic phenotype so called “‘lineage infidelity”, entailing a wide spread co-expression of otherwise lineage restricted genes. Our study revealed lineage infidelity is functionally required for SCs to cope with stress and maintain malignancy. Curiously, rather than a cancer specific phenomenon, lineage infidelity occurs in wounded SCs, and is essential for wound repair. Of importance, it signifies a state where lineage genes are re-wired from a homeostatic network into a stress-specific one, presumably in cooperation of stress-induced genes, at the level of chromatin and non-coding regulatory elements. Our most recent observations suggest lineage infidelity occurs across many diseases and stress conditions including aging, hence may represent a core mechanism SCs use to steer fate choices.

The second part of our research aims to interrogate the non-coding regulatory sequences as drivers of human diseases. So called the “genomic dark matter”, non-coding sequences comprise 98.5% of the human genome and remains largely uncharted, especially in terms of their functional significance. Given our own observations of the dramatic remodeling of these non-coding regulatory elements during SC response in wound repair and cancer, it is intriguing to postulate their mis-function may lead to human diseases. Recent advance in high throughput sequencing and CRISPR technology provided unprecedented opportunities to gain mechanistic insights into these questions. As proof of principle, we characterized one group of such noncoding products, microRNAs (miRNAs) -- evolutionarily conserved, abundant, small non-coding RNAs that regulate gene expression at post-transcriptional level. Using ultrasound-guided in utero lentiviral microinjections, we carried out in vivo high throughput functional screen, through which we identified novel oncogenic miRNAs that drive the progression of skin SCCs. Recently, we’ve combined this system with CRISPR to achieve lineage specific and inducible knockout, overexpression, enhancer bashing, and lineage tracing to dissect molecular and cellular mechanisms underlying wound repair and cancer. Such rapid, stable and tissue specific transgene integration enables functional genomics at a hitherto unparalleled speed and precision. Our long-term goal is to leverage the basic knowledge we learn from human data and mouse models to therapeutically benefit patients with degenerative and malignant diseases.